JP2008518015A - Phosphonate-substituted kinase inhibitor - Google Patents

Abstract

The present invention is useful for preparing such conjugates as well as therapeutic methods involving the administration of phosphorus-substituted kinase inhibitor conjugates, compositions containing such conjugates, and administration of such conjugates. Process and intermediates. Assay methods that can measure the presence, absence or amount of kinase inhibition are practically useful for diagnosing the presence of pathologies associated with kinase activity as well as the search for kinase inhibitors. Such inhibitors have therapeutic uses, for example, as anticancer agents.

Description

(Related application)
This patent document claims priority from the following US provisional patent applications, all of which were filed on October 26, 2004, the contents of all of which are incorporated herein by reference. 60 / 623,098; 60 / 622,992; 60 / 622,881; 60 / 622,960; 60 / 622,811; 60 / 622,942; and 60 / 622,943.

(Field of Invention)
The present invention relates generally to phosphonate-containing compounds having kinase inhibitory activity, ie, compounds that inhibit at least one kinase.

(Background of the Invention)
Improved delivery of drugs and other drugs to target cells and tissues has been the focus of many years of research. Despite many attempts to develop effective methods of transferring bioactive molecules into cells both in vivo and in vitro, none has been proven to be completely satisfactory. For example, it is often difficult or inefficient to optimize the binding of an inhibitory drug to its intracellular target while minimizing intercellular redistribution of the drug to surrounding cells.

  Most drugs currently administered parenterally to patients are not targeted, thereby delivering systemic drugs to cells and tissues in the body that are unnecessary and often undesirable. This systemic delivery can result in drug side effects, often limiting the dose of drug that can be administered. According to comparison, oral administration of drugs is generally recognized as a simple and economical method of administration. However, oral administration of a drug may (a) take up the drug through cell and tissue barriers (eg, blood / brain barrier, epithelium, cell membrane), resulting in undesirable systemic distribution, and / or (b) in the gastrointestinal tract Can be either transiently present in the drug. Thus, the main objective is to develop a method that specifically targets drugs to cells and tissues. The benefits of such treatment include avoiding the common physiological effects of inappropriate delivery of such agents to other cells and tissues (eg, uninfected cells).

  Therefore, improved pharmacological properties (eg, improved kinase inhibitory activity and / or pharmacological properties (including improved oral bioavailability)), greater potency and prolonged effects in vivo There is a need for therapeutic agents with a typical half-life (eg, agents that inhibit at least one kinase). Such inhibitors have therapeutic uses, for example, as anticancer agents. Therefore, new kinase inhibitors should have fewer side effects, less complex dosing schedules, and be orally active. In particular, there is a need for less cumbersome dosing regimens (eg, once a day, one pill).

  Assay methods that can measure the presence, absence or amount of kinase inhibition are practically useful for diagnosing the presence of pathologies associated with kinase activity as well as the search for kinase inhibitors.

(Summary of specific embodiments of the present invention)
Intracellular targeting can be achieved by methods and compositions that allow the accumulation or retention of biologically active agents within the cell. Certain embodiments of the invention provide novel analogs of kinase inhibitory compounds, ie compounds that inhibit the activity of at least one kinase. Such novel kinase inhibitory analogs have the utility of kinase inhibitory compounds and provide cellular accumulation as needed. In addition, certain embodiments of the present invention provide compositions and methods useful for inhibiting at least one kinase that may have therapeutic activity against diseases associated with kinase activity (eg, cancer). provide.

  The present invention generally relates to intracellular accumulation or retention of therapeutic compounds. More specifically, the present invention relates to the acquisition of high concentrations of phosphonate-containing molecules in target cells. Such effective targeting may be applicable to various therapeutic formulations and procedures.

  The composition of the present invention contains a kinase inhibitory compound having at least one phosphonate group. Accordingly, in one embodiment, the present invention provides a conjugate containing a compound linked to one or more phosphonate groups; or a pharmaceutically acceptable salt or solvate thereof.

  In another embodiment, the invention provides a compound comprising at least one phosphonate group and a substructure of any one of formulas 100-106, or a pharmaceutically acceptable salt thereof:

ここで：

here:

で表わされる結合は、単結合または二重結合である；
Ｒ^２９は、水素、アルキル、または−Ｃ（＝Ｏ）Ｒ^３６である；
Ｒ^３０は、水素または置換アルキルである；そして
Ｒ^３１およびＲ^３２は、別個に、水素、アルキル、または置換アリールである；あるいはＲ^３１およびＲ^３２は、それらが結合する窒素原子と一緒になって、置換または非置換複素環を形成する；
Ｒ^３３は、−Ｏ−、−ＮＲ^３５−または存在しない；
Ｒ^３４は、−Ｏ−または存在しない；
Ｒ^３５は、水素またはアルキルである；
Ｒ^３６は、水素、アルキル、アルケニル、またはアルキニルである；
Ｒ^５６は、−Ｎ−、または−ＣＲ^６８である；そして
Ｒ^６８は、水素またはアルキルである、
化合物、またはそれらの薬学的に受容可能な塩。

The bond represented by is a single bond or a double bond;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl; and R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² are taken together with the nitrogen atom to which they are attached. Form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁶ is —N— or —CR ⁶⁸ ; and R ⁶⁸ is hydrogen or alkyl.
A compound, or a pharmaceutically acceptable salt thereof.

  The present invention provides pharmaceutical compositions containing an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

  The present invention provides a method of enhancing cell accumulation and retention of drug compounds, thereby improving their therapeutic and diagnostic value, wherein the method comprises one or more (eg, one) of said compounds. 2, 3, or 4) phosphonate groups.

  The invention also provides a method of inhibiting the activity of at least one kinase, the method comprising administering to a mammal an amount of a compound of the invention.

  The invention also includes compounds of the invention for use in drug therapy (preferably for use in treating conditions associated with kinase activity (eg, high kinase activity)) as well as conditions associated with kinase activity. Provided is the use of a compound of the invention for the manufacture of a medicament useful for treating (eg, a condition associated with high kinase activity). The present invention also provides the use of a compound of the present invention for the preparation of a medicament for treating cancer in an animal.

  The present invention also provides the methods and novel intermediates disclosed herein that are useful for preparing the compounds of the present invention. Some of the compounds of the present invention are useful for preparing other compounds of the present invention.

  In another aspect of the invention, the activity of the kinase is inhibited by a method comprising the step of treating a sample suspected of containing the kinase with a compound or composition of the invention.

(Detailed description of the invention)
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying description, structures and formulas. While the invention has been described in connection with the enumerated claims, it will be understood that they are not to be construed as limiting the invention to these embodiments. On the contrary, the invention is to be construed as including all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined in the embodiments.

  Many of the current treatment regimens for cell proliferative disorders (eg, psoriasis and cancer) utilize compounds that block DNA synthesis. Such compounds are toxic to cells in general, but their toxic effects on rapidly dividing cells (eg, tumor cells) can be beneficial. Alternative approaches to anti-proliferative agents that act by mechanisms other than the inhibition of DNA synthesis may show high sensitivity of action.

  Recently, it has been discovered that cells can become cancerous by transforming part of their DNA into oncogenes (ie, genes that, when activated, cause the formation of malignant tumor cells) (Bradshaw, Mutagenesis). 1986, 1, 91). Some such oncogenes cause the production of peptides that are receptors for growth factors. This growth factor receptor complex subsequently increases cell proliferation. For example, some oncogenes encode tyrosine kinase enzymes, and certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsen et al. Ann.Reports in Med.Chem. 1989, Chpt. 13).

  Receptor tyrosine kinases are important in the transmission of biochemical signals that initiate cellular replication. They are large enzymes that span the cell membrane and have an extracellular binding domain of a growth factor (eg, epidermal growth factor (EGF)) and an intracellular portion that functions as a kinase or phosphorylated tyrosine amino acid in the protein. Thus affecting cell proliferation. Various types of receptor tyrosine kinases based on a family of growth factors that bind to different receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73). This classification includes class I receptor tyrosine kinases, including the EGF family of receptor tyrosine kinases (eg, EGF, TGFa, NEU, erbB, Xmrk, HER and let23 receptors), class II receptor tyrosine kinases (which include , The insulin family of receptor tyrosine kinases (including, for example, insulin, IGFI and insulin-related receptors (IRR)), and class III receptor tyrosine kinases (which include the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases (eg, PDGFα, PDGFβ and colony-stimulating factor 1 (CSF1) receptor).

  Class I kinases (eg, the EGF family of receptor tyrosine kinases) are often found in routine human cancers such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988). , 3, 21 and Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung cancer (NSCLC) (adenocarcinoma (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al.). Int. J. Cancer, 1990, 45, 269; and Rusch et al., Cancer Research, 1993, 53, 2379) and squamous cell carcinoma of the lung (Hendler et al., Cancer Cells, 1989, 7). 347)), bladder cancer (Neal et al., Lancet, 1985, 366), esophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer (eg, colorectal cancer, rectal cancer or gastric cancer) (Bolen et al., Oncogene Res., 1987, 1, 149), prostate cancer (Visakorpi et al., Histochem. J., 1992, 24, 481), leukemia (Konaka et al., Cell, 1984, 37, 1035) and ovarian cancer, It is present in bronchial cancer or pancreatic cancer (European Patent Specification No. 0400586). As other human tumor tissues are being tested for the EGF family of receptor tyrosine kinases, it is expected that their prevalence has been established in other cancers (eg, thyroid cancer and uterine cancer). The EGF type tyrosine kinase activity is rarely detected in normal cells, whereas it is more frequently detected in malignant cells. (Hunter, Cell, 1987, 50, 823). EGF receptors with tyrosine kinase activity are found in many human cancers (eg brain tumors, lung squamous cell carcinomas, bladder cancers, gastric cancers, breast cancers, head and neck tumors, esophageal cancers, gynecological cancers and thyroid cancers. ) (W. J. Gullick, Brit. Med. Bull., 1991, 47, 87).

  Thus, inhibitors of receptor tyrosine kinases are therefore valuable as selective inhibitors of mammalian cancer cell growth (Yaish et al., Science, 1988, 242, 933). This view is supported by the fact that elvstatin, an EGF receptor tyrosine kinase, specifically reduces the growth of transplanted human breast cancer that expresses EGF receptor tyrosine kinase in athymic nude mice, but expresses EGF receptor tyrosine kinase. Provided by proof that it has no effect on the growth of other cancers (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722). Various derivatives of styrene also have tyrosine kinase inhibitory properties (European Patent Applications 0 211 363, 0 304 493 and 0 322 738) and can be used as anticancer agents. The in vivo inhibitory effects of these two styrene derivatives, which are EGF receptor tyrosine kinase inhibitors, have been demonstrated against the growth of human squamous cell carcinoma inoculated in nude mice (Yoneda et al., Cancer Research, 1991, 51, 4430). Various known tyrosine kinase inhibitors are described in T.W. R. Burke Jr. (Drugs of the Future, 1992, 17, 119).

  Kinase inhibitors have valuable pharmacological properties and can be used, for example, as anticancer agents and as drugs against atherosclerosis. Protein phosphorylation has long been known as an important step in cell differentiation and proliferation. Phosphorylation is catalyzed by protein kinases classified as serine / threonine kinases and tyrosine kinases. These serine / threonine kinases include protein kinase C, and tyrosine kinases include PDGF (platelet derived growth factor) receptor tyrosine kinase and Bcr-Abl kinase.

  Chronic myeloid leukemia (CML) is known as the Philadelphia chromosome, which is detected in 95% of patients with CML and 20% of patients with acute lymphocytic leukemia (ALL) Is a hematological stem cell disorder associated with specific chromosomal translocations. The molecular result of this translocation is a fusion to the abl protooncogene bcr gene, which results in the production of an activated form of the Abl tyrosine protein kinase. This Bcr-Abl protein can induce leukemia in mice and therefore implicates this protein as the cause of these diseases. Therefore, kinase inhibitors inhibit cellular kinases (eg, Bcr-Abl) that are involved in disease states. Inhibitors are useful treatments for these disorders because the tyrosine kinase activity of this Bcr-Abl protein is essential for its conversion activity.

  In addition, kinase inhibitors prevent the development of resistance (eg, multidrug resistance) in cancer treatment using other chemotherapeutic drugs, or eliminate existing resistance to other chemotherapeutic drugs.

  Two processes, the new formation of blood vessels from differentiated endothelial cells or hemangioblasts in the developing embryo (angiogenesis) and the growth of new capillaries from existing blood vessels (angiogenesis), It is involved in the development of vasculature in animal organs and tissues. Transient phases of new blood vessel formation (neovascularization) also occur in the adult body, for example during the menstrual cycle, pregnancy and wound healing. On the other hand, many diseases are known in connection with deregulated angiogenesis (eg, retinopathy, psoriasis, hemangioblastoma, hemangioma, and neoplastic disease (eg, solid tumors)). It has been discovered that the complex process of angiogenesis and angiogenesis involves cell adhesion molecules as well as a full range of molecules, particularly vasogenic growth factors and their endothelial receptors.

  Recent discoveries indicate that the cellular receptor is at the center of a network that regulates the growth and differentiation of the vasculature and its components, and in a wide number of physiological abnormalities and diseases, both during embryonic development and normal growth. And angiogenic factors known as vascular endothelial growth factor (VEGF) have been identified (Breier, G. et al., Trends in Cell Biology 6,454-6 (1996) and therein. (See cited references).

  VEGF is a dimeric disulfide-linked 46-kDa glycoprotein and is related to platelet derived growth factor (PDGF). It is produced by normal and tumor cell lines, is an endothelial cell-specific mitogen, exhibits angiogenic activity in in vivo test systems (eg, rabbit cornea), and chemotaxis to endothelial cells and monocytes And induces plasminogen activator in endothelial cells, which in turn is involved in proteolysis of the extracellular matrix during the formation of capillaries. Many isoforms of VEGF show similar biological activity, but differ in the types of cells that secrete them and their ability to bind heparin. In addition, there are other members of the VEGF family, such as placental growth factor (PLGF) and VEGF-C.

  The VEGF receptor is a transmembrane receptor tyrosine kinase. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptors (eg, VEGFR-1, VEGFR-2 and VEGFR-3) are known.

  Many human tumors (especially gliomas and carcinomas) express high levels of VEGF and its receptors. Thereby, VEGF released by the tumor cells stimulates capillary growth and tumor endothelium proliferation in a paracrine manner, thus accelerating tumor growth with improved blood supply.

  Increased VEGF expression can explain the appearance of brain edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenic factor in vivo was obtained in studies where VEGF expression or VEGF activity was blocked. This has been achieved with the use of antibodies that inhibit VEGF activity, dominant negative VEGFR-2 mutants that suppress signaling, or antisense-VEGF RNA technology. All approaches caused decreased growth of glioma cell lines or other tumor cell lines as a result of suppressed tumor angiogenesis.

  In addition, hypoxia, a number of growth factors and cytokines (eg, epithelial cell growth factor, transforming growth factor a, transforming growth factor A, interleukin 1, and interleukin 6) are expressed in VEGF in cell experiments. Induces expression. Angiogenesis is considered a requirement for tumor cells growing beyond a maximum diameter of about 1-2 mm; to this limit, oxygen and nutrients can be supplied to the tumor cells by diffusion. Therefore, any tumor, regardless of its origin and its cause, is thought to depend on angiogenesis for its growth after reaching a certain size.

  The following three major mechanisms play an important role in the activity of angiogenesis inhibitors against tumors: 1) Due to the balance achieved between apoptosis and proliferation, the result is the absence of net tumor growth, Prevention of growth of blood vessels (especially capillaries) into avascular resting tumors; 2) prevention of tumor cell migration due to the absence of blood flow from and to the tumor; and 3) endothelial cells Inhibition of proliferation, thereby avoiding the paracrine growth stimulating effect added to surrounding cells by endothelial cells that normally line blood vessels.

  Inhibitors of cyclin-dependent kinases (eg, Alvocidiv (US Pat. No. 4,900,727; also known as flavopiridol) are found in various cancers (gastrointestinal and colon cancer, leukemia and It has been identified as a therapeutic that may be useful for (including myeloma) (see, for example, Intl. J. Oncol., 1996, 9, 1143).

  Inhibitors of tyrosine kinases (including Bcr-Abl (eg, Gleevec)) treat chronic myeloid leukemia (CML) and potentially other cancers that express these kinases (acute lymphocytic leukemia ( ALL) and certain solid tumors). Gleevec has been approved for the treatment of inoperable and / or metastatic malignant gastrointestinal stromal tumors (GISTs).

  Inhibitors of Flt3 tyrosine kinase (eg, CEP-701 (US Pat. No. 4,923,986) and Midostaurin (US Pat. No. 5,093,330) may be useful in the treatment of various cancers. (Cancer Res., 1999, 59, 10).

  Inhibitors of MAP Erk kinase (eg, PD-184352) (US Pat. No. 6,251,943) are useful for a variety of oncological disorders, including colon cancer, breast cancer, pancreatic cancer and non-small cell lung cancer (See for example Proc. Am. Soc. Clin. Oncol., 2003, 22, abstract 816).

  Other kinase inhibitors, such as dramapimod (US Pat. No. 6,319,921), are treatments that may be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. It has been identified as a drug.

  Other kinase inhibitors (eg, BAY-43-9006) (US Publication No. 2002/0165394) may be useful in the treatment of various cancers, including gastrointestinal cancer and colon cancer, leukemia and carcinoma. It has been identified as a potential therapeutic (Curr. Pharm. Design, 2002, 8, 2269).

  Cytokine receptors are important for immune cell development and homeostasis. All of these receptors require the cytoplasmic tyrosine kinase JAK3 for signal transduction (Changelian, PS et al., Science, 2003, 302, 875). CP-690,550 (WO 02,096,909) is an orally available Janus kinase (JAK) -3 inhibitor for potential treatment of graft rejection and psoriasis.

  Therefore, improved pharmacological properties (eg, agents with improved kinase inhibitory activity and / or pharmacological properties (including improved oral bioavailability)), greater potency and longer in vivo There is a need for therapeutic agents that are kinase inhibitors with a reduced effective half-life. Such inhibitors have therapeutic potential, for example as anticancer agents. The kinase inhibitor compounds provided herein include, for example, breast cancer, non-small cell lung cancer (NSCLCs), adenocarcinoma, squamous cell carcinoma of the lung, esophageal cancer, gastrointestinal cancer, colon cancer, rectal cancer, stomach cancer, prostate Other to treat cancer, leukemia, ovarian cancer, bronchial cancer, pancreatic cancer, thyroid cancer, uterine cancer, brain tumor, lung squamous cell carcinoma, bladder cancer, stomach cancer, head and neck cancer, gynecological cancer and thyroid cancer To prevent the development of resistance in cancer treatment using chemotherapeutic drugs (eg multidrug resistance) or against other chemotherapeutic drugs, retinopathy, hemangioblastoma, hemangioma and neoplastic disease, glioma To block tumor angiogenesis, myeloma, chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), inoperable and / or metastatic malignant gastrointestinal stromal tumors (GISTs) to eliminate resistance Inflammatory diseases (eg joints) Rheumatic, treatment of Crohn's disease), the treatment of cell proliferative disorders, as well as graft rejection and treatment of psoriasis; may be used to prepare and medicaments for such treatment.

(Definition)
Unless otherwise stated, the following terms and phrases as used herein are to be interpreted as having the following meanings:
When using a trade name, the applicant intends to separately include the product of that trade name and the active pharmaceutical ingredient of the product of that trade name.

  “Bioavailability” is the extent to which a pharmaceutically active agent is made available to the target tissue after it is introduced into the body. Increasing the bioavailability of a pharmaceutically active agent makes more of the pharmaceutically active agent available to the target tissue site for a given dose or more, thus making the patient more efficient and effective Can be treated.

  The terms “phosphonate” and “phosphonate group” are phosphorus (1) single bonded to carbon, 2) double bonded to heteroatom, and 3) single bonded to heteroatom. And 4) a single bond to another heteroatom, wherein each heteroatom includes a functional group or moiety in the molecule that contains the same or different). The terms “phosphonate” and “phosphonate group” can also be separated from a compound such that the compound contains a phosphorus having the above characteristics, as well as a functional group or moiety containing phosphorus in the same oxidation state as the phosphorus. It contains a functional group or moiety that contains a prodrug moiety. For example, the terms “phosphonate” and “phosphonate group” include phosphoric acid, phosphoric monoester, phosphoric diester, phosphonamidate and phosphonthioate functional groups. In one particular embodiment of the invention, the terms “phosphonate” and “phosphonate group” are phosphorus (which is 1) single bonded to carbon and 2) double bonded to oxygen, 3 A compound so that it contains phosphorus having the above properties as well as functional groups or moieties in the molecule that contain a) a single bond to oxygen and 4) a single bond to other oxygen) A functional group or moiety containing a prodrug moiety that can be separated from In another particular embodiment of the invention, the terms “phosphonate” and “phosphonate group” are phosphorus (which is 1) single bonded to carbon and 2) double bonded to oxygen. 3) single bond to oxygen or nitrogen, and 4) single molecule to other oxygen or nitrogen) as well as functional groups or moieties in the molecule, the compound has such properties It contains a functional group or moiety that contains a prodrug moiety that can be separated from the compound to contain phosphorus.

  As used herein, the term “prodrug” refers to a drug substance (ie, as a result of spontaneous chemical reaction, enzyme-catalyzed chemical reaction, photolysis and / or metabolic chemical reaction when administered to a biological system. Active compound) means any compound that yields. Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds.

  “Prodrug moiety” means a labile functional group that separates from an active inhibitor compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage or some other process. (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, 1991, P. Krogsgard, H., B. Bloggard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development. Enzymes that enable an enzyme activation mechanism with the phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase and phosphatase. Prodrug moieties can serve to increase solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A prodrug moiety may include an active metabolite or drug itself.

Exemplary prodrug moieties include hydrolysis sensitive or unstable acyloxymethyl esters —CH ₂ OC (═O) R and acyloxymethyl carbonate —CH ₂ OC (═O) OR, where R is , C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl. This acyloxyalkyl ester was first used as a prodrug scheme for carboxylic acids and was then used by Farquar et al. (1983) J. MoI. Pharm. Sci. 72: 324; also applied to phosphates and phosphonates according to US Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756. Subsequently, this acyloxyalkyl ester was used to deliver phosphonic acid across the cell membrane to enhance oral bioavailability. Alkoxycarbonyloxyalkyl ester (carbonate), a variant close to this acyloxyalkyl ester, can also enhance oral bioavailability as a prodrug moiety in compounds of the present formulation. A representative acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH ₂ OC (═O) C (CH ₃ ) ₃ . A representative acyloxymethyl carbonate prodrug moiety is pivaloyloxymethyl carbonate (POC) —CH ₂ OC (═O) OC (CH ₃ ) ₃ .

  The phosphonate group can be a phosphonate prodrug moiety. The prodrug moiety can be susceptible to hydrolysis, such as, but not limited to, pivaloyloxymethyl carbonate (POC) or POM groups. Alternatively, the prodrug moiety may be susceptible to enzyme-enhanced cleavage, such as a lactate ester group or a phosphonamidate ester group.

  Phosphorus aryl esters (especially phenyl esters) have been reported to increase oral bioavailability (DeLambert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic acid ester ortho to the phosphate have also been described (Khamnei and Torrance, (1996) J. Med. Chem. 39: 4109-4115). Benzyl esters have been reported to yield their parent phosphonic acid. In some cases, substituents at the ortho or para position may facilitate hydrolysis. A benzylic analog with an acylated phenol or an alkylated phenol can yield this phenolic compound by the action of an enzyme (eg, esterase, oxidase, etc.), which in turn undergoes cleavage at the benzyl C—O bond. To produce phosphoric acid and quinone methide intermediates. Examples of this type of prodrug are described in Mitchell et al. (1992) J. MoI. Chem. Soc. Perkin Trans. II345; Glazier WO 91/19721. Still other benzyl prodrugs have been described, which contain a carboxylic ester containing group attached to its benzylmethylene (Glazier WO 91/19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group, where the thiol group is esterified with an acyl group or combined with other thiol groups to form disulfides. De-esterification or reduction of this disulfide yields the free thio intermediate, which subsequently decomposes into phosphate and episulfide (Puch et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. ( 1996) J. Med. Chem. 39:25 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al., US Pat. No. 6,312,662).

  “Protecting group” means a portion of a compound that masks or alters the properties of the functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. For example, “Protective Groups in Organic Chemistry”, Theodora W. See Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often utilized to mask the reactivity of certain functional groups to aid in the effectiveness of the desired chemical reaction, for example to create and break chemical bonds in an ordered manner. Protection of the functional group of the compound alters other physical properties (eg, polarity, lipophilicity (hydrophobicity), and other properties that can be measured by conventional analytical means) other than the reactivity of the protected functional group. Chemically protected intermediates can themselves be biologically active or inactive.

  Protected compounds may also exhibit altered (in some cases optimized) properties in vitro and in vivo (eg, resistance to cell membrane passage and enzymatic degradation or chelate formation). In this role, protected compounds with the desired therapeutic effect can be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, which releases the parent drug when the prodrug is converted in vivo. A prodrug can have a higher potency in vivo than its parent drug because the active prodrug can be absorbed more effectively than the parent prodrug. Protecting groups are removed either in vitro for chemical intermediates or in vivo for prodrugs. For chemical intermediates, it is not particularly important that the products (eg, alcohols) obtained after deprotection are physiologically acceptable, but generally they are pharmacologically harmless. desirable.

Reference to any of the compounds of the present invention includes reference to their physiologically acceptable salts. Physiologically acceptable salts of the compounds of the present invention include suitable bases (eg, alkali metals (eg, sodium), alkaline earth metals (eg, magnesium), ammonium and NX ₄ ⁺ (where X is , C ₁ -C ₄ alkyl))). Physiologically acceptable salts of hydrogen atoms or amino groups include organic carboxylic acids (eg acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid. Acid); organic sulfonic acids (eg methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid); and salts of inorganic acids (eg hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid). For physiologically acceptable salts of compounds having a hydroxyl group, suitable cations (eg, Na ⁺ and NX ^4+, where X is independently selected from H or a C ₁ -C ₄ alkyl group) ) And the anion of the compound in combination.

  For therapeutic use, the active ingredient salts of the compounds of the invention are physiologically acceptable, i.e. they are derived from a physiologically acceptable acid or base. However, salts of acids or bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts are within the scope of the present invention, whether derived from physiologically acceptable acids or bases.

As used herein, the term “substructure” refers to a residue that has been removed or removed so that any hydrogen atom or substitutable group provides an open valence for substitution of a group comprising a phosphonate group. Meaning, for example, this substructure is a scaffold to which the substituent-link-P (O) (OR ¹ ) ₂ is bound. These substructures can have additional groups attached. For kinase inhibitor compounds comprising at least one phosphonate group and a substructure, it is understood that the compound includes this substructure as at least part of the overall structure of the compound.

“Alkyl” is a C ₁ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples include methyl (Me, _-CH 3), ethyl _{(Et, -CH 2 CH 3)} , 1- propyl (n-Pr, _{n-propyl, -CH 2 CH 2 CH 3)} , 2- propyl (i -pr, _{i-propyl, -CH (CH 3) 2)} , 1- butyl (n-Bu, n- _{butyl, -CH 2 CH 2 CH 2 CH} 3), 2- methyl-1-propyl (i-Bu , i- _{butyl, -CH 2 CH (CH 3)} 2), 2- butyl (s-Bu, s- _{butyl, -CH (CH 3) CH 2} CH 3), 2- methyl-2-propyl (t- Bu, t-butyl, —C (CH ₃ ) ₃ ), 1-pentyl (n-pentyl, —CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (—CH (CH ₃ ) CH ₂ CH ₂ CH _3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 2- Methyl-2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl-2-butyl _{(-CH (CH 3) CH (} CH 3) 2), 3- methyl-1-butyl (- _{CH 2 CH 2 CH (CH 3} ) 2), 2- methyl-1-butyl _{(-CH 2 CH (CH 3)} CH 2 CH 3), 1- hexyl _{(-CH 2 CH 2 CH 2 CH} 2 CH 2 CH _3), 2-hexyl _{(-CH (CH 3) CH 2} CH 2 CH 2 CH 3), 3- hexyl _{(-CH (CH 2 CH 3)} (CH 2 CH 2 CH 3)), 2- methyl-2 - pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl _{(-CH (CH 3) CH (} CH 3) CH 2 CH 3), 4- methyl-2-pentyl _{(-CH (CH 3) CH 2} CH (CH 3) 2 ), 3-methyl-3-pentyl _{(-C (CH 3) (CH} 2 CH 3) 2), 2- methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2 , 3-dimethyl-2-butyl (—C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (—CH (CH ₃ ) C (CH ₃ ) ₃ .

“Alkenyl” is a C ₂ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation (ie, carbon-carbon, sp ² double bond). is there. Examples include but are not limited to: ethylene or vinyl (—CH═CH ₂ ), allyl (—CH ₂ CH═CH ₂ ), cyclopentenyl (—C ₅ H ₇ ) and 5-hexenyl. _{(-CH 2 CH 2 CH 2 CH} 2 CH = CH 2).

“Alkynyl” is a C ₂ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation (ie, carbon-carbon, sp triple bond). Examples include, but are not limited to: acetylenic (—C≡CH) and propargyl (—CH ₂ C≡CH).

“Alkylene” is a saturated branched or straight chain or cyclic hydrocarbon radical of C _{1 to} C ₁₈ carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Which has two monovalent radical centers derived from the above. Typical alkylene radicals include, but are not limited to: methylene (—CH ₂ —), 1,2-ethyl (—CH ₂ CH ₂ —), 1,3-propyl (—CH ₂ CH ₂ CH ₂ -), 1,4- butyl _{(-CH 2 CH 2 CH 2 CH} 2 -) and the like.

“Alkenylene” is an unsaturated branched or straight chain or cyclic hydrocarbon radical of C _{2 to} C ₁₈ carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkene. Means having two monovalent radical centers induced by Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (—CH═CH—).

“Alkynylene” is an unsaturated branched or straight chain or cyclic hydrocarbon radical of C _{2 to} C ₁₈ carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Means having two monovalent radical centers induced by Typical alkynylene radicals include, but are not limited to: acetylene (—C≡C—), propargyl (—CH ₂ C≡C—) and 4-pentynyl (—CH ₂ CH ₂ CH ₂ C≡CH—).

  “Aryl” means a monovalent hydrocarbon radical of 6 to 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” means an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom) is replaced with an aryl radical. Typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthobenzyl, 2-naphthphenylethane-1-yl, and the like, It is not limited to these. An arylalkyl group contains 6 to 20 carbon atoms, for example, its alkyl moiety (eg, an alkanyl, alkenyl, or alkynyl group of an arylalkyl group) has 1 to 6 carbon atoms. And the aryl moiety has from 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl” and “substituted arylalkyl” mean alkyl, aryl and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include but are not limited ^{to: -X, -R, -O -,} - OR, -SR, -S -, -NR 2, -NR 3, = NR, _{-CX 3, -CN, -OCN, -SCN} , -N = C = O, -NCS, -NO, -NO 2, = N 2, -N 3, NC (= O) R, -C (= O ^{_{) R, -C (= O)}} NRR-S (= O) 2 O -, -S (= O) 2 OH, -S (= O) 2 R, -OS (= O) 2 OR, -S ( _{= O) 2 NR, -S (} = O) R, -OP (= O) O 2 RR, -P (= O) O 2 RR-P (= O) (O -) 2, -P (= O ) (OH) ₂ , —C (═O) R, —C (═O) X, —C (S) R, —C (O) OR, —C (O) O—, —C (S) OR , -C (O) SR, -C (S) SR, -C (O) NRR, -C (S) RR, -C (NR) NRR, wherein each X is independently halogen: F, Cl, Br or I; and each R is independently -H, alkyl, aryl, complex A ring, or a prodrug moiety. Alkylene, alkenylene and alkynylene groups can be substituted as well.

  As used herein, “heterocycle” includes, but is not limited to, the heterocycles described in the following references: Paquette, Leo A. et al. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), in particular, chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Heterocyclic." Wiley & Sons, New York, 1950 to present), in particular, 13, 14, 16, 19 and 28; Am. Chem. Soc. (1960) 82: 5566. In one particular embodiment of the invention a “heterocycle” comprises a carbocycle as defined herein, wherein one or more (eg 1, 2, 3 or 4). ) Is replaced by a heteroatom (eg, O, N or S).

  Examples of heterocycles include, but are not limited to, the following: pyridyl, dihydroxypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, tetrahydrothiophenyl sulfurate, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl , Imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroxyl Nolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1, , 2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthalidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, flazadinyl, furazinyl , Chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazi Nyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl and bis-tetrahydrofuranyl:

限定ではなく例として、炭素が結合した複素環は、ピリジンの２、３、４、５または６位置、ピリダジンの３、４、５または６位置、ピリミジンの２、４、５または６位置、ピラジンの２、３、５または６位置、フラン、テトラヒドロフラン、チオフラン、チオフェン、ピロールまたはテトラヒドロピロールの２、３、４または５位置、オキサゾール、イミダゾールまたはチアゾールの２、４または５位置、イソオキサゾール、ピラゾールまたはイソチアゾールの３、４または５位置、アジリジンの２または３位置、アゼチジンの２、３または４位置、キノリンの２、３、４、５、６、７または８位置、またはイソキノリンの１、３、４、５、６、７または８位置で結合される。さらに典型的には、炭素が結合した複素環には、２−ピリジル、３−ピリジル、４−ピリジル、５−ピリジル、６−ピリジル、３−ピリダジニル、４−ピリダジニル、５−ピリダジニル、６−ピリダジニル、２−ピリミジニル、４−ピリミジニル、５−ピリミジニル、６−ピリミジニル、２−ピラジニル、３−ピラジニル、５−ピラジニル、６−ピラジニル、２−チアゾリル、４−チアゾリルまたは５−チアゾリルが挙げられる。

By way of example and not limitation, a carbon-attached heterocycle may be 2, 3, 4, 5 or 6 position of pyridine, 3, 4, 5 or 6 position of pyridazine, 2, 4, 5 or 6 position of pyrimidine, pyrazine 2, 3, 5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole 2, 3, 4 or 5 position, oxazole, imidazole or thiazole 2, 4 or 5 position, isoxazole, pyrazole or 3, 4, or 5 position of isothiazole, 2 or 3 position of aziridine, 2, 3 or 4 position of azetidine, 2, 3, 4, 5, 6, 7 or 8 position of quinoline, or 1, 3, of isoquinoline Joined at 4, 5, 6, 7 or 8 positions. More typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

  By way of example and not limitation, nitrogen-attached heterocycles include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazolin. , 3-pyrazoline, piperidine, piperazine, indole, indoline, 1 position of 1H-indazole, 2 position of isoindole or isoindoline, 4 position of morpholine, 9 position of carbazole or β-carboline. More typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.

  “Carbocycle” means a saturated, unsaturated or monocyclic ring having from 3 to 7 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicycle and up to about 20 carbon atoms as a polycycle. An aromatic ring is meant. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 to 6 ring atoms. Bicyclic carbocycles are composed of 7 to 12 ring atoms (these are arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system. Or 9 or 10 ring atoms, which are arranged as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, phenyl, spiryl and naphthyl.

"Linker" or "link" means a chemical moiety that contains a covalent bond or a chain of atoms or groups that are covalently attached to a phosphonate group or drug. The linker includes moieties of substituents A ¹ and A ³ , which include, for example, the following repeating unit moieties: alkyloxy (eg, polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino ( For example, polyethyleneamino, Jeffamine®); and diacid esters and amides (including succinates, succinamides, diglycolates, malonates and caproamides).

  The term “chiral” refers to molecules that have the non-superimposable properties of their mirror image partners, while the term “achiral” refers to molecules that are superimposable with their mirror image partners.

  The term “stereoisomer” means compounds that have the same chemical structure but differ with respect to the arrangement of atoms in space.

  "Diastereomer" means a stereoisomer with two or more chiral centers but whose molecules are not mirror images of one another. Diastereomers have different physical properties (eg, melting points, boiling points, spectral properties, and reactivity). Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

  “Enantiomer” means two stereoisomers of a compound that are not superimposable on each other.

  The term “treatment” or “treating” to the extent related to a disease or condition prevents the occurrence of the disease or condition, prevents the disease or condition, and / or eliminates the disease or condition, and / or Including alleviating one or more symptoms of the disease or condition.

  The stereochemical definitions and conventions used in this specification are the P. Parker, Ed. McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E .; and Wilen, S .; , Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc. , New York. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarization. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (−) are used to specify the sign of rotation of plane polarized light by the compound, (−) or l means that the compound is levorotatory. To do. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are the same except that they are mirror images of one another. Certain stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures, which are stereoselective or stereospecific in chemical reactions or processes. Can occur if there is no. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate. The terms “racemic mixture” and “racemic compound” mean an equimolar mixture of two enantiomeric species, which lack optical activity.

(Protecting group)
In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.

  Commonly known and used protecting groups are available, which can be optionally combined with the protecting group during synthetic procedures (ie, pathways or methods for preparing the compounds of the invention). Used to prevent side reactions. In most cases, the determination of which groups to protect, when to protect, and the nature of the chemical protecting group “PRT” (eg, acidic state, basic state, oxidized state, reduced state or other state) Depending on the chemical nature of the reaction to be protected against and the intended direction of its synthesis. These PRT groups need not be the same and are generally not the same if the compound is substituted with multiple PRTs. In general, PRT is used to protect functional groups (eg, carboxyl groups, hydroxyl groups, thio groups, or amino groups), thereby preventing side reactions or otherwise promoting synthesis efficiency. Is done. The order of deprotection to yield a free deprotecting group depends on the intended direction of synthesis and the reaction conditions encountered and can occur in any order determined by one skilled in the art.

  Various functional groups of the compounds of the invention can be protected. For example, protecting groups for —OH groups (whether hydroxyl, carboxylic acid, phosphonic acid or other functional groups) include “ether or ester forming groups”. Ether or ester forming groups can function as chemical protecting groups in the synthetic schemes shown herein. However, some hydroxyl and thio protecting groups are not ether- or ester-forming groups, as will be appreciated by those skilled in the art, and are included with amides as described below.

  A very large number of hydroxyl protecting groups and amide-forming groups and the corresponding chemical cleavage reactions are described in “Protective Groups in Organic Synthesis”, Theodora W. et al. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-63021-6) ("Green"). Also, Kocienski, Philip J. et al. See "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994), the contents of which are incorporated herein by reference. Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxy Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117C 154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other acid protecting groups, see Greene below. Such groups include, but are not limited to, esters, amides, hydrazines, and the like.

(Ether and ester protecting groups)
Ester forming groups include: (1) phosphonate ester groups (eg, phosphonamidate esters, phosphonthioate esters, phosphonate esters, and phosphon-bis-amidates); (2) carboxyl ester forming groups, and ( 3) Sulfur ester forming groups (eg sulfonates, sulfates and sulfinates).

  The phosphonate moiety of the compounds of the invention may or may not be a prodrug moiety, i.e. they may or may not undergo hydrolytic cleavage or enzymatic cleavage or denaturation. Certain phosphonate moieties are stable under almost or almost all metabolic conditions. For example, a dialkyl phosphonate (again, the alkyl group is 2 or more carbons) may have adequate stability in vivo due to the slow rate of hydrolysis.

In connection with phosphonate prodrug moieties, a number of structurally diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)), which are Included within the scope of the invention. An exemplary phosphonate ester-forming group is a phenyl carbocycle in substructure A ₃ having the following formula:

ここで、Ｒ_１は、ＨまたはＣ_１〜Ｃ_１２アルキルであり得る；ｍ１は、１、２、３、４、５、６、７または８であり、そして該フェニル炭素環は、０個〜３個のＲ_２基で置換されている。また、Ｙ_１がＯである実施態様では、乳酸エステルが形成され、Ｙ_１がＮ（Ｒ_２）、Ｎ（ＯＲ_２）またはＮ（Ｎ（Ｒ_２）_２である場合、ホスホンアミデートエステルが得られる。

Where R ₁ can be H or C ₁ -C ₁₂ alkyl; m 1 is 1, 2, 3, 4, 5, 6, 7 or 8 and the phenyl carbocycle has 0 to Substituted with 3 R ₂ groups. Also, in embodiments where Y ₁ is O, when a lactic acid ester is formed and Y ₁ is N (R ₂ ), N (OR ₂ ) or N (N (R ₂ ) ₂ , the phosphonamidate ester is can get.

In its ester-forming role, the protecting group is typically attached to any acidic group (eg, by way of example and not limitation, a —CO ₂ H or —C (S) OH group), whereby — CO ₂ R ^x is obtained, where R ^x includes, for example, ester groups listed in WO 95/07920.

Examples of protecting groups include the following:
C ₃ -C ₁₂ heterocycle (described above) or aryl. These aromatic groups are polycyclic or monocyclic as required. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4 -And 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl Listed;
Substituted below the _C 3 _{-C 12} heterocycle or aryl: _{^{halo, R 1, R 1 -O-}} C 1 ~C 12 _alkylene, C 1 _{-C 12} alkoxy, _CN, NO 2, OH, carboxy, carboxy ester , thiol, _thioesters, C 1 _{-C 12} haloalkyl (1 to 6 halogen _atoms), C 2 _{-C 12} alkenyl or _C 2 _{-C 12} alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C ₁ -C ₁₂ alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2, 3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy -4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4 -Dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (2-, 3- and 4-fluorophenyl and 2-, 3- and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2) , 5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3, 5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl (2,4-difluorophenyl and 3,5-difluorophenyl including in), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen _atoms, including C 1 _{-C 12} alkyl (4-trifluoromethylphenyl)), 2-, 3- and 4 -Cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloa Kirubenjiru (one to five halogen _atoms, C 1 _{-C 12} alkyl (4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl including in)), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkyl salicylic phenyl _(C 1 -C ₄ alkyl, 2-, 3- and 4 -Including ethyl salicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (—C ₁₀ H ₆ —OH) and aryloxyethyl [C ₆ -C ₉ aryl (phenoxyethyl Including)), 2,2′-sihydroxybiphenyl, 2-, 3- and 4-N, N-dialkylaminophenol, —C _{6 H 4 CH 2 -N (CH} 3) 2, trimethoxybenzyl, triethoxysilane benzyl, 2-alkylpyridinyl _{(C 1 to 4} alkyl);

；２−カルボキシフェニルのＣ_４〜Ｃ_８エステル；および置換Ｃ_１〜Ｃ_４アルキレン−Ｃ_３〜Ｃ_６アリール（ベンジル、−ＣＨ_２−ピロリル、−ＣＨ_２−チエニル、−ＣＨ_２−イミダゾリル、−ＣＨ_２−オキサゾリル、−ＣＨ_２−イソキサゾリル、−ＣＨ_２−チアゾリル、−ＣＨ_２−イソチアゾリル、−ＣＨ_２−ピラゾリル、−ＣＨ_２−ピリジニルおよび−ＣＨ_２−ピリミジニルを含めて）であって、これは、そのアリール部分において、３個〜５個のハロゲン原子または１個〜２個の以下から選択される原子または基で置換されている：ハロゲン、Ｃ_１〜Ｃ_１２アルコキシ（メトキシおよびエトキシを含めて）、シアノ、ニトロ、ＯＨ、Ｃ_１〜Ｃ_１２ハロアルキル（１個〜６個のハロゲン原子）；−ＣＨ_２ＣＣｌ_３を含めて）、Ｃ_１〜Ｃ_１２アルキル（メチルおよびエチルを含めて）、Ｃ_２〜Ｃ_１２アルケニルまたはＣ_２〜Ｃ_１２アルキニル；アルコキシエチル［Ｃ_１〜Ｃ_６アルキル（−ＣＨ_２−ＣＨ_２−Ｏ−ＣＨ_３（メトキシエチル）を含めて）］；置換アルキルであって、これは、アリールについて上で示した基のいずれか、特に、ＯＨまたは１個〜３個のハロ原子で置換されている（−ＣＨ_３、−ＣＨ（ＣＨ_３）_２、−Ｃ（ＣＨ_３）_３、−ＣＨ_２ＣＨ_３、−（ＣＨ_２）_２ＣＨ_３、−（ＣＨ_２）_３ＣＨ_３、−（ＣＨ_２）_４ＣＨ_３、−（ＣＨ_２）_５ＣＨ_３、−ＣＨ_２ＣＨ_２Ｆ、−ＣＨ_２ＣＨ_２Ｃｌ、−ＣＨ_２ＣＦ_３および−ＣＨ_２ＣＣｌ_３を含めて）；

; _C 4 -C ₈ esters of 2-carboxyphenyl; and substituted _C 1 -C ₄ alkylene _-C 3 -C ₆ aryl (benzyl, -CH ₂ - pyrrolyl, -CH ₂ - thienyl, -CH ₂ - imidazolyl - CH ₂ - oxazolyl, -CH ₂ - isoxazolyl, -CH ₂ - thiazolyl, -CH ₂ - isothiazolyl, -CH ₂ - pyrazolyl, -CH ₂ - pyridinyl and -CH ₂ - a pyrimidinyl a included), which The aryl moiety is substituted with 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the following: halogen, C ₁ -C ₁₂ alkoxy (including methoxy and ethoxy) ), cyano, nitro, _OH, C 1 _{-C 12} haloalkyl (1 to 6 halogen atoms); _- CH 2 CCl _{3 including), C} 1 ~C ₁₂ alkyl (including methyl and _{ethyl), C} 2 ~C ₁₂ alkenyl or _C 2 _{-C 12} alkynyl; alkoxy ethyl _[C 1 -C ₆ alkyl _(-CH 2 -CH ₂ -O-CH 3, including _{(methoxyethyl));} a substituted alkyl, this is one of the groups indicated above for aryl, especially substituted by OH or 1 to 3 halo atoms has been is _{(-CH 3, -CH (CH 3} ) 2, -C (CH 3) 3, -CH 2 CH 3, - (CH 2) 2 CH 3, - (CH 2) 3 CH 3, - ( _{CH 2) 4 CH 3, -} (CH 2) 5 CH 3, -CH 2 CH 2 F, -CH 2 CH 2 Cl, a _-CH 2 CF ₃ and _-CH 2 CCl ₃ including);

−Ｎ−２−プロピルモルホリノ、２，３−、ジヒドロ−６−ヒドロキシインデン、セサモール、カテコールモノエステル、−ＣＨ_２−Ｃ（Ｏ）−Ｎ（Ｒ^１）_２、−ＣＨ_２−Ｓ（Ｏ）（Ｒ^１）、−ＣＨ_２−Ｓ（Ｏ）_２（Ｒ^１）、−ＣＨ_２−ＣＨ（ＯＣ（Ｏ）ＣＨ_２Ｒ^１）−ＣＨ_２（ＯＣ（Ｏ）ＣＨ_２Ｒ^１）、コレステリル、エノールピルベート（ＨＯＯＣ−Ｃ（＝ＣＨ_２）−）、グリセロール；
５個または６個の炭素単糖類、二糖類またはオリゴ糖類（３個〜９個の単糖類残基）；
トリグリセリド（例えば、α−Ｄ−β−ジグリセリド）（ここで、グリセリド脂質を構成する脂肪酸は、一般に、天然に生じる飽和または不飽和Ｃ_６〜２６、Ｃ_６〜１８またはＣ_６〜１０脂肪酸（例えば、リノール酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、パルミトイル酸、リノレン酸などの脂肪酸）である）であって、これらは、そのトリグリセリドのグリセリル酸素を介して、その親化合物のアシルに結合している；
リン脂質であって、これは、リン脂質のホスフェートを介して、カルボキシル基に結合している；
フタリジル（これは、Ｃｌａｙｔｏｎら、Ａｎｔｉｍｉｃｒｏｂ．Ａｇｅｎｔｓ Ｃｈｅｍｏ．（１９７４）５（６）：６７０−６７１の図１で示されている）；
環状カーボネート（例えば、（５−Ｒ_ｄ−２−オキソ−１，３−ジオキソレン−４−イル）メチルエステル（Ｓａｋａｍｏｔｏら、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．（１９８４）３２（６）２２４１−２２４８）であって、ここで、Ｒ_ｄは、Ｒ_１、Ｒ_４またはアリールである）；および

-N-2-propyl-morpholino, 2,3, dihydro-6-hydroxy-indene, sesamol, catechol ^{_{monoester, -CH 2 -C (O) -N}} (R 1) 2, -CH 2 -S (O) (R ¹ ), —CH ₂ —S (O) ₂ (R ¹ ), —CH ₂ —CH (OC (O) CH ₂ R ¹ ) —CH ₂ (OC (O) CH ₂ R ¹ ), cholesteryl, pyruvate _{(HOOC-C (= CH 2} ) -), glycerol;
5 or 6 carbon monosaccharides, disaccharides or oligosaccharides (3 to 9 monosaccharide residues);
Triglycerides (e.g., alpha-D-beta-diglycerides) (wherein the fatty acids composing glyceride lipids generally occurs naturally saturated or unsaturated _C 6 to _{26, C having 6 to 18} or _{C 6 to 10} fatty acids (e.g. Fatty acids such as linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoyl acid, linolenic acid), which are their parent compounds via the glyceryl oxygen of their triglycerides Bound to the acyl of
A phospholipid, which is linked to the carboxyl group via the phosphate of the phospholipid;
Phthalidyl (this is shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo. (1974) 5 (6): 670-671);
A cyclic carbonate (eg, (5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al., Chem. Pharm. Bull. (1984) 32 (6) 224-1248). Wherein R _d is R ₁ , R ₄ or aryl); and

本発明の化合物の水酸基は、必要に応じて、ＷＯ９４／２１６０４で開示されたＩＩＩ基、ＩＶ基またはＶ基の１個で置換されているか、またはイソプロピルで置換されている。

The hydroxyl group of the compounds of the present invention is optionally substituted with one of the III, IV or V groups disclosed in WO 94/21604 or substituted with isopropyl.

Table A lists examples of protecting group ester moieties that can be attached to, for example, a —C (O) O— or —P (O) (O—) ₂ group via oxygen. Some amidates are also shown, which are directly attached to -C (O)-or -P (O) ₂ . Esters of structures 1-5, 8-10 and 16, 17, 19-22 have a free hydroxyl group in DMF (or other solvents such as acetonitrile or N-methylpyrrolidone) The compound can be converted to the corresponding halide (such as chloride or acyl chloride) and N, N-dicyclohexyl-N-morpholinecarboxamidine (or other bases such as DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc. )) And is synthesized. When the protecting compound is a phosphonate, the esters of structures 5-7, 11, 12, 21 and 23-26 are alcohols or alkoxide salts thereof (or corresponding amines in the case of compounds such as 13, 14 and 15). Is reacted with monochlorophosphonate or dichlorophosphonate (or other activated phosphonate).

＃−キラル中心は、（Ｒ）、（Ｓ）またはラセミ化合物である。

The # -chiral center is (R), (S) or a racemate.

  Other esters suitable for use herein are described in EP 63,2048.

Protecting groups also contain “double bond” forming pro-functionalities (eg, the following): —CH ₂ OC (O) OCH ₃ ,

−ＣＨ_２ＳＣＯＣＨ_３、−ＣＨ_２ＯＣＯＮ（ＣＨ_３）_２、または構造−ＣＨ（Ｒ^１またはＷ^５）Ｏ（（ＣＯ）Ｒ^３７）または−ＣＨ（Ｒ^１またはＷ^５）（（ＣＯ）Ｒ^３８）のアルキル−またはアリール−アシルオキシアルキル基（これらは、その酸性基の酸素に結合している）であって、ここで、Ｒ^３７およびＲ^３８は、アルキル、アリールまたはアルキルアリール基である（米国特許第４９６８７８８を参照）。しばしば、Ｒ^３７およびＲ^３８は、嵩張った基（例えば、分枝アルキル、オルト−置換アリール、メタ−置換アリール、またはそれらの組合せ（１個〜６個の炭素原子を有するノルマル、第二級、イソおよび第三級アルキルを含めて））である。一例には、ピバロイルメチル基がある。このような有用な保護基の例には、アルキルアシルオキシメチルエステルおよびそれらの誘導体があり、これらには、（−ＣＨ（ＣＨ_２ＣＨ_２ＯＣＨ_３）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、

_{-CH 2 SCOCH 3, -CH 2 OCON} (CH 3) 2 or the structure -CH ^{(R 1} or ^{W 5), O ((CO} ) R 37) or -CH ^{(R 1} or ^W 5) ((CO) R ³⁸ ) alkyl- or aryl-acyloxyalkyl groups, which are attached to the oxygen of the acidic group, wherein R ³⁷ and R ³⁸ are alkyl, aryl or alkylaryl groups ( See U.S. Pat. No. 4,968,788). Often R ³⁷ and R ³⁸ are bulky groups (eg, branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof (normal, secondary having 1-6 carbon atoms, secondary , Including iso and tertiary alkyl))). An example is a pivaloylmethyl group. Examples of such useful protecting groups include alkylacyloxymethyl esters and their derivatives, which include (—CH (CH ₂ CH ₂ OCH ₃ ) OC (O) C (CH ₃ ) ₃ ,

−ＣＨ_２ＯＣ（Ｏ）Ｃ_１０Ｈ_１５、−ＣＨ_２ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ（ＣＨ_２ＯＣＨ_３）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ（ＣＨ（ＣＨ_３）_２）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＯＣ（Ｏ）Ｃ_６Ｈ_１１、−ＣＨ_２ＯＣ（Ｏ）Ｃ_６Ｈ_５、−ＣＨ_２ＯＣ（Ｏ）Ｃ_１０Ｈ_１５、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２ＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３および−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２Ｃ_６Ｈ_５が挙げられる。

_{-CH 2 OC (O) C 10} H 15, -CH 2 OC (O) C (CH 3) 3, -CH (CH 2 OCH 3) OC (O) C (CH 3) 3, -CH (CH ( _{CH 3) 2) OC (O} ) C (CH 3) 3, -CH 2 OC (O) CH 2 CH (CH 3) 2, -CH 2 OC (O) C 6 H 11, -CH 2 OC (O _{) C 6 H 5, -CH 2} OC (O) C 10 H 15, -CH 2 OC (O) CH 2 CH 3, -CH 2 OC (O) CH (CH 3) 2, -CH 2 OC (O ) C _{(CH 3) 3} and _{-CH 2 OC (O) CH 2} C 6 H 5 and the like.

  In some embodiments, the protected acidic group is an ester of the acidic group and is the residue of a hydroxy-containing functional group. In other embodiments, amino compounds are used to protect this acid functionality. Suitable hydroxyl or amino-containing functional group residues are found in WO 95/07920. Amino acids, amino acid esters, polypeptides or aryl alcohols are particularly important. Exemplary amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L1 or L2 groups on pages 11-18 of WO 95/07920 and associated text. WO 95/07920 explicitly teaches amidates of phosphonic acids, but it has been found that such amidates are formed with any of the acid groups indicated herein, the amino acid residues of which are It is shown in WO95 / 07920.

Typical esters for protecting acid functional groups are also described in WO 95/07920 and again, like the phosphonates of this' 920 publication, using the acid groups herein, the same ester is It can be seen that it can be formed. Typical ester groups are defined at least in WO 95/07920, pages 89-93 (R ³¹ or R ³⁵ ), page 105, and pages 21-23 (as R). Unsubstituted aryl such as phenyl or arylalkyl (eg benzyl), or hydroxy-, halo-, alkoxy-, carboxy- and / or alkylester carboxy-substituted aryl or alkylaryl (especially phenyl, ortho-ethoxyphenyl or C ₁ -C ₄ alkyl ester carboxyphenyl (salicylic acid C ₁ -C ₁₂ alkyl ester)) is of particular importance.

  This protected acidic group is useful as a prodrug for oral administration, particularly when using the esters or amides of WO95 / 07920. However, it is not essential to protect this acid group in order to effectively administer the compounds of the invention by the oral route. Compounds of the invention having protecting groups (particularly amino acid amidates or substituted and unsubstituted aryl esters) can be hydrolytically cleaved in vivo when administered systemically or orally to give the free acid.

  One or more of the acidic hydroxyls are protected. If more than one acidic group is protected, the same or different protecting groups can be used, for example, their esters can be the same or different, or mixed amidates and esters can be used.

Typical hydroxy protecting groups described in Greene (pages 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters (including sulfonate esters and carbonates). For example:
Ether (methyl, t-butyl, allyl);
Substituted methyl ether (methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacol methyl, t-butoxymethyl 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromo Tetrahydropyranyl, tetrahydropthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropthiopyranyl S, S-dio 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));
Substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoro Ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl);
Substituted benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p, p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl , Di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4′-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ′, 4 ″ -tris (4,5-dichloro Phthalimidophenyl) methyl, 4,4 ', 4 "-tris (levulinoyloxy) Phenyl) methyl, 4,4 ′, 4 ″ -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylethyl) bis (4 ′, 4 ″ -dimethoxyphenyl) methyl, 1,1-bis (4- Methoxyphenyl) -1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide);
Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, Diphenylmethylsilyl, t-butylmethoxyphenylsilyl);
Esters (formate ester, benzoyl formate, acetate ester, chloroacetate ester, dichloroacetate ester, trichloroacetate ester, trifluoroacetate ester, methoxyacetate ester, triphenylmethoxyacetate ester, phenoxyacetate ester, p-chlorophenoxyacetate ester, p Poly-phenylacetic acid ester, 3-phenylpropionic acid ester, 4-oxopentanoic acid ester (levulinic acid ester), 4,4- (ethylenedithio) pentanoic acid ester, pivalic acid ester, adamantate, crotonic acid ester, 4 -Methoxycrotonate, benzoate, p-phenyl benzoate, 2,4,6-trimethyl (mesitoate) benzoate);
Carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2 (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, Allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl, methyldidithiocarbonate) ;
Groups that aid cleavage (2-iodobenzoate, 4-azide butyrate, 4-nitro-4-methyl pentanoate, o- (dibutyromethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (Methylthiomethoxy) butyrate, 2 (methylthiomethoxymethyl) benzoate); miscellaneous esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethyl) (Butyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigroate), o- (methoxycarbonyl) Benzoate, p-poly-ben , Α-naphthonate, nitrate ester, alkyl N, N, N ′, N′-tetramethyl phosphorodiamidate, N-phenylcarbamate, borate ester, dimethylphosphinothioyl, 2,4-dinitrophenyl sulfenate ); And sulfonates (sulfate, methyl sulfonate (mesylate), benzyl sulfonate, tosylate).

  Typical 1,2-diol protecting groups (and therefore generally when two OH groups are combined with protecting functional groups) are described in Greene pages 118-142, which include cyclic Acetals and ketals (methylene, ethylidene, 1-tert-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene , Cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene; cyclic orthoester (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene) 1-ethoxy Tyridine, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, α- (N, N-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); silyl derivative (Di-t-butylsilylene group, 1,3- (1,1,3,3-tetraisopropyldisiloxanilidene) and tetra-t-butoxydisiloxane-1,3-diylidene), cyclic carbonate, cyclic boronate , Ethyl boronate and phenyl boronate.

  More typically, 1,2-diol protecting groups include those shown in Table B, more typically epoxides, acetonides, cyclic ketals and aryl acetates.

ここで、Ｒ^９は、Ｃ_１〜Ｃ_６アルキルである。

Here, R ⁹ is C ₁ -C ₆ alkyl.

(Amino protecting group)
Another set of protecting groups includes any of the typical amino protecting groups described in Greene, pages 315-385. They include the following:
Carbamate: (methyl and ethyl, 9-fluorenylmethyl, 9 (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di-t-butyl- [ 9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl, 4-methoxyphenacyl);
Substituted ethyl: (2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1- Dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butyl Phenyl) -1-methylethyl, 2- (2′- and 4′-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl , Cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitroben Le, p- bromobenzyl, p- chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinyl benzyl, 9-anthrylmethyl, diphenylmethyl);
Groups that aid in cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethyl Thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxybonyl) benzyl, 5-benzisoxazolylmethyl 2- (trifluoromethyl) -6-chromonylmethyl);
Groups capable of photolytic cleavage: (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); urea type derivatives (pheno Thiazinyl- (10) -carbonyl, N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);
Miscellaneous carbamates: (t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- ( N, N-dimethylcarboxamido) benzyl, 1,1-dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropynyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl, Iodobornyl, isobutyl, isonicotinyl, p- (p′-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5- Dimethoxyphenyl) Eth 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2, 4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl, 2,4,6-trimethylbenzyl);
Amide: (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, Np-phenylbenzoyl);
Amides that aid in cleavage: (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4- Chlorobutyryl, N-3-methyl-3-nitrobutyryl, No-nitrocinnamoyl, N-acetylmethionine, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, 4,5-diphenyl-3 -Oxazolin-2-one);
Cyclic imide derivatives: (N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleyl oil, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilyl Azacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexane-2- ON, 1-substituted 3,5-dinitro-4-pyridonyl);
N-alkyl and N-arylamines: (N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro-2- Oxo-3-pyrrolin-3-yl), quaternary ammonium salt, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N- (4- Methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N′-oxide);
Imine derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N, (N ′, N ′ -Dimethylaminomethylene, N, N-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl) phenylmethylene, N-cyclohex Silidene);
Enamine derivatives: (N- (5,5-dimethyl-3-oxo-1-cyclohexenyl));
N-metal derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl (pentacarbonylchromium-or-tungsten)] carbenyl, N-copper or N-zinc chelates);
NN derivatives: (N-nitro, N-nitroso, N-oxide);
NP derivatives: (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkylphosphoryl, N-dibenzylphosphoryl, N-diphenylphosphoryl);
N-Si derivatives, NS derivatives and N-sulfenyl derivatives: (N-benzenesulfenyl, No-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N 2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl derivatives (Np-toluenesulfonyl, N-benzenesulfonyl, N- 2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N- 2,3,5,6-tetramethyl-4-methoxybenzenesulfonate N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman -6-sulfonyl, N-methanesulfonyl, N-β-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N- Trifluoromethylsulfonyl, N-phenacylsulfonyl).

More typically, protected amino groups include carbamates, amidines and amides, even more typically —NHC (O) OR ¹ , —NHC (O) R ¹ or —N═CR ¹ N (R ¹ ₂ ). Other protecting groups useful as prodrugs for amino or —NH (R ⁵ ) include the following:

例えば、Ａｌｅｘａｎｄｅｒ、Ｊ．ら（１９９６）Ｊ．Ｍｅｄ．Ｃｈｅｍ．３９：４８０−４８６を参照。

For example, Alexander, J. et al. (1996) J. et al. Med. Chem. 39: 480-486.

(Amino acid and polypeptide protecting groups and conjugates)
The amino acid or polypeptide protecting group of the compounds of the invention has the structure R ¹⁵ NHCH (R ¹⁶ ) C (O) —, where R ¹⁵ is H, an amino acid or a polypeptide residue, or R ⁵ and R ¹⁶ is defined below.

R ¹⁶ is lower alkyl or lower alkyl (C ₁ -C ₆ ), which is amino, carboxyl, amide, carboxyl ester, hydroxyl, C ₆ -C ₇ aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide and And / or alkyl phosphate. R ¹⁶ is also taken together with the amino acid α-N to form a proline residue (R ¹⁶ = —CH ₂ ) ₃ —). However, R ¹⁶ is generally a naturally occurring amino acid (eg, H, —CH ₃ , —CH (CH ₃ ) ₂ , —CH ₂ —CH (CH ₃ ) ₂ , —CHCH ₃ —CH ₂ —CH ₃ , _{-CH 2 -C 6 H 5, -CH} 2 CH 2 -S-CH 3, -CH 2 OH, -CH (OH) -CH 3, -CH 2 -SH, -CH 2 -C 6 H 4 OH, _{-CH 2 -CO-NH 2, -CH} 2 -CH 2 -CO-NH 2, -CH 2 -COOH, -CH 2 -CH 2 -COOH, - (CH 2) 4 -NH 2 and - (CH ₂ ) ₃ -NH-C (NH ₂ ) -NH ₂ ) side chain. R ¹⁶ also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Other sets of protecting groups include amino-containing compounds, particularly amino acids, polypeptides, protecting groups —NHSO ₂ R, NHC (O) R, —N (R) ₂ , NH ₂ or —NH (R) (H ) Such that, for example, a carboxylic acid is reacted (ie, coupled) with the amine to form an amide, such as C (O) NR ₂ . Phosphonic acid may be reacted with the amine, as in -P (O) (OR) ( NR 2), to form a phosphonamidate,
In general, an amino acid has the structure R ¹⁷ C (O) CH (R ¹⁶ ) NH—, where R ¹⁷ is —OH, —OR, an amino acid, or a polypeptide residue. Amino acids are low molecular weight compounds of the order of less than about 1000 MW, which contain at least one amino or imino group and at least one carbonyl group. In general, this amino acid is found in nature, i.e. it can be detected in biological material (e.g. bacteria or other microorganisms, plants, animals or humans). Suitable amino acids are typically characterized by an alpha amino acid, ie, one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Compound. Hydrophobic residues (eg mono- or di-alkyl or aryl amino acids, cycloalkyl amino acids, etc.) are particularly important. These residues contribute to the permeability of the cell by increasing the partition coefficient of its parent drug. Typically, this residue does not contain a sulfhydryl or guanidino substituent.

  Naturally occurring amino acid residues include those found in nature in plants, animals or microorganisms, particularly those proteins. Polypeptides are most typically composed essentially of such naturally occurring amino acid residues. These amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and There is hydroxyproline. In addition, unnatural amino acids such as balanine, phenylglycine and homoarginine are also included. Commonly encountered non-gene encoded amino acids can also be used in the present invention. All of the amino acids used in the present invention can be either the D- or L-optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. et al. F. , In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B .; By Weinstein, Marcel Dekker, New York, p. 267 (1983).

When the protecting group is a single amino acid residue or polypeptide, it is optionally substituted with R ³ of the substituent A ¹ or A ³ in the compound of the present invention. These conjugates are generally generated by forming an amide bond between the carboxyl groups of that amino acid (or, for example, the C-terminal amino acid of a polypeptide). Similarly, conjugates between the amino group of R ³ and amino acid or polypeptide, is formed. In general, only one of the optional sites in the parent molecule is amidated with an amino acid as described herein, but introducing an amino acid with more than one permissive site is Within the scope of the invention. Usually, the carboxyl group of R ³ is amidated with an amino acid. In general, the α-amino or α-carboxyl group of the amino acid or the terminal amino or carboxyl group of the polypeptide is attached to the parent functional group, ie the carboxyl group or amino group of the amino acid side chain is generally It is not used to form amide bonds with compounds (though these groups may need to be protected during the synthesis of these conjugates, as further described below).

With respect to the side chain of the amino acid or carboxy-containing polypeptide, it can be seen that this carboxyl group is blocked, eg, by R ¹ , esterified with R ⁵ , or amidated, as appropriate. Similarly, the amino side chain R ¹⁶ is optionally blocked with R ¹ or substituted with R ⁵ .

  Such ester or amide linkages with side chain amino groups or carboxyl groups are subject to acidic (pH <3) or basic (pH> 10) conditions as required, such as the ester or amide with its parent molecule. Underneath, it can be hydrolyzed in vivo or in vitro. Alternatively, they are substantially stable in the human gastrointestinal tract, but are enzymatically hydrolyzed in the blood or intracellular environment. These esters or amino acids or polypeptide amidates are also useful as intermediates for preparing parent molecules containing free amino or carboxyl groups. The free acid or base of the parent compound is readily formed from the ester or amino acid or polypeptide conjugates of the invention, for example, by conventional hydrolysis procedures.

  When an amino acid residue contains one or more chiral centers, its D, L, meso, threo or erythro (when appropriate) racemate, scalemate compound or mixtures thereof can be used. In general, the D isomer is useful if these intermediates are hydrolyzed (as is the case when their amides are used as chemical intermediates for organic acids or free amines). On the other hand, the L isomer is more versatile because it is susceptible to both non-enzymatic and enzymatic hydrolysis and is more efficiently transported by the amino acid or dipeptidyl transport system in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R ^x or R ^y include the following:
glycine;
Aminopolycarboxylic acids (for example, aspartic acid, β-hydroxyaspartic acid, glutamic acid, -hydroxyglutamic acid, β-methylaspartic acid, β-methylglutamic acid, β, β-dimethylaspartic acid, γ-hydroxyglutamic acid, γ-dihydroxy Glutamic acid, β-phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids (eg arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylysine and diaminobutyric acid;
Other basic amino acid residues (eg histidine);
Diaminodicarboxylic acids (eg, α, α′-diaminosuccinic acid, α, α′-diaminoglutaric acid, α, α′-diaminoadipic acid, α, α′-diaminopimelic acid, α, α′-diamino-β- Hydroxypimelic acid, α, α′-diaminosuberic acid, α, α′-diaminoazelineic acid and α, α′-diaminosebacic acid;
Imino acids (eg, proline, hydroxyproline, allohydroxyproline, γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid and azetidine-2-carboxylic acid);
Mono- or di-alkyl (typically C ₁ -C ₈ branched or normal) amino acids (eg alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptillin, α-methylserine, α-amino) -Α-methyl-γ-hydroxyvaleric acid, α-amino-α-methyl-δ-hydroxyvaleric acid, α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamic acid, α-aminoisobutyric acid , Α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n- Propyl acetic acid, α-aminoisoamyl acetic acid, α-methyl aspartic acid, α-methyl glutamic acid, - amino cyclopropane-1-carboxylic acid, isoleucine, allo-isoleucine, tert-leucine, beta-methyl tryptophan and α- amino -β- ethyl -β- phenylpropionic acid;
β-phenylselinyl;
Aliphatic α-amino-β-hydroxy acids (eg, serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline and α-amino-β-hydroxystearic acid);
α-amino, α-, β-, γ- or ε-hydroxy acids (eg homoserine, δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues); canabin and canalin; γ-hydroxy Ornithine;
2-hexosamic acid (eg, D-glucosamic acid or D-galactosamic acid);
α-amino-β-thiol (eg penicillamine, β-thionorvaline or β-thiobutyrin);
Other sulfur-containing amino acid residues (cysteine; homocystin, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol ethers of cysteine or homocysteine);
Phenylalanine, tryptophan and ring-substituted α-amino acids (including, for example, phenyl- or cyclohexyl amino acids, α-aminophenylacetic acid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid); phenylalanine analogs and derivatives ( This includes aryl, lower alkyl, hydroxy, guanidino, oxyalkyl ether, nitro, sulfur or halo-substituted phenyl (eg tyrosine, methyltyrosine and o-chloro, p-chloro-, 3,4-dichloro) O-, m- or p-methyl, 2,4,6-trimethyl, 2-ethoxy-5-nitro, 2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thionyl-, pyridyl , Pyrimidinyl-, purinyl- Or naphthyl-alanine; and tryptophan analogs and derivatives (including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan);
α-amino substituted amino acids (including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline) ); And α-hydroxy and substituted α-hydroxy amino acids (including serine, threonine, arosleonine, phosphoserine and phosphothreonine).

  A polypeptide is a polymer of amino acids, where the carboxyl group of one amino acid monomer is linked to the amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, lower polypeptides (about 1500-5000 MW) and proteins. The protein optionally contains 3, 5, 10, 50, 75, 100 or more residues, and suitably human, animal, plant or microbial proteins. The sequence is substantially homologous. They include not only enzymes (eg, hydrogen peroxide degrading enzymes) but also immunogens (eg, KLH or any type of antibody or protein for which it is desired to enhance the immune response). The nature and identity of this polypeptide can vary widely.

  Polypeptide amidases are immunized in raising antibodies against either the polypeptide (if not the immunogen in the animal to which it is administered) or the antigenic determinant on the remainder of the compounds of the invention. Useful as a source.

  Antibodies capable of binding to the parent non-peptidyl compound are used to separate the parent compound from the mixture, eg, in the diagnosis or manufacture of the parent compound. The conjugate of the parent compound and the polypeptide is generally more immunogenic than the polypeptide in closely homologous animals, and thus the polypeptide is made more effective to promote the induction of antibodies against the polypeptide. Make it immunogenic. Thus, the polypeptide or protein may not need to be immunogenic in animals typically used to raise antibodies (eg, rabbits, mice, horses, or rats), but the final product The conjugate should be immunogenic in at least one such animal. The polypeptide optionally includes a peptide lytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzyme recognition structures (eg, specific sequences of residues recognized by peptide lytic enzymes).

Peptide lytic enzymes for cleaving the polypeptide conjugates of the present invention are well known and include, in particular, carboxypeptidases. Carboxypeptidases that digest polypeptides by removing C-terminal residues are often specific for specific C-terminal sequences. Such enzymes and their general substrate requirements are well known. For example, a dipeptide (having a given residue pair and a free carboxy terminus) is covalently bonded to the phosphorus atom or carbon atom of the compounds herein through its α-amino group. In embodiments where W ₁ is a phosphonate, it is expected that the peptide will be cleaved by the appropriate peptide lytic enzyme, leaving the carboxyl of the proximal amino acid residue, and the phosphonoamidate bond cleaved autocatalytically. The

  Suitable dipeptidyl groups (indicated by their one letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW , AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN , ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG , DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM , CF, CP, CS, CT, CW, CY, CV, EA, R, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, M, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, T D, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, There are VY and VV.

Tripeptide residues are also useful as protecting groups. If the phosphonate is to be protected, the sequence -X ⁴ -pro-X ^5- (X ⁴ is any amino acid residue and X ⁵ is an amino acid residue, a carboxyl ester of proline, or hydrogen ) is is cleaved by luminal carboxypeptidase, produce X ⁴ with a free carboxyl, X ⁴ having the free carboxyl is then expected to autocatalytically cleave the phosphonoamidate bond. Carboxy group of X ⁵ optionally is esterified with benzyl.

  Dipeptide species or tripeptide species can be selected based on known transport properties and / or sensitivity to peptidases that can affect transport to intestinal mucosal cell types or other cell types. Dipeptides and tripeptides lacking an α-amino group are transport substrates for peptide transporters found in the brush border membrane of intestinal mucosal cells (Bai, JPF, (1992) Pharm Res. 9: 969- 978). Thus, transport competent peptides can be used to enhance the bioavailability of the amidate compound. Dipeptides or tripeptides having one or more amino acids of form D are also compatible with peptide transport and can be utilized in the amidate compounds of the invention. D-form amino acids can be used to reduce the sensitivity of dipeptides or tripeptides to hydrolysis by proteases common to brush borders (eg, aminopeptidase N). In addition, the dipeptide or tripeptide is alternatively selected based on its relative resistance to hydrolysis by proteases found in the intestinal lumen. For example, a tripeptide or polypeptide lacking asp and / or glu is a poor quality substrate for aminopeptidase A and is an amino acid residue on the N-terminal side of a hydrophobic amino acid (leu, tyr, phe, val, trp) A dipeptide or tripeptide lacking is a poor substrate for endopeptidase, and a peptide lacking the penultimate pro residue at the free carboxyl terminus is a poor substrate for carboxypeptidase P. Similar considerations also apply to the selection of peptides that are either relatively resistant or relatively sensitive to hydrolysis by cytosolic peptidases, kidney peptidases, liver peptidases, serum peptidases, or other peptidases. obtain. Such poorly cleaved polypeptides amidates are immunogens or are useful for binding to proteins to prepare immunogens.

(Specific Embodiments of the Invention)
Not only are the specific values describing radicals, substituents and ranges, but also the specific embodiments of the invention described herein are presented by way of example only; Or other values within the specified range are not excluded.

  In one particular embodiment, the invention provides a compound comprising at least one phosphonate group and a substructure of formula 100, or a pharmaceutically acceptable salt thereof:

ここで：

here:

で表わされる結合は、単結合または二重結合である；
別の特定の実施態様では、本発明は、少なくとも１個のホスホネート基と次式の下部構造とを含む化合物を提供する：

The bond represented by is a single bond or a double bond;
In another specific embodiment, the present invention provides a compound comprising at least one phosphonate group and a substructure of the formula:

ここで：
Ｒ^２０およびＲ^２１は、別個に、水素、アルキル、置換アルキル、アリールまたは置換アリールである；
Ｒ^２２は、存在しない、水素、アルキル、または置換アルキルである；
Ｒ^２３は、Ｏ、または−ＮＲ^２５Ｒ^２６である；
Ｒ^２４は、アリールまたは置換アリールである；
Ｒ^２５は、水素またはアルキルである；
Ｒ^２６は、水素、アルキル、または−Ｃ（＝Ｏ）ＮＲ^２７Ｒ^２８である；
Ｒ^２７およびＲ^２８は、別個に、水素、アルキル、または置換アルキルである；そして

here:
R ²⁰ and R ²¹ are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R ²² is absent, hydrogen, alkyl, or substituted alkyl;
R ²³ is O, or —NR ²⁵ R ²⁶ ;
R ²⁴ is aryl or substituted aryl;
R ²⁵ is hydrogen or alkyl;
R ²⁶ is hydrogen, alkyl, or —C (═O) NR ²⁷ R ²⁸ ;
R ²⁷ and R ²⁸ are independently hydrogen, alkyl, or substituted alkyl; and

で表わされる結合は、単結合または二重結合である；ここで、Ｒ^２２は、

The bond represented by is a single bond or a double bond; wherein R ²² is

で表わされる結合が二重結合であるとき、存在しない。本発明の別の特定の実施態様では、Ｒ^２０は、水素である；Ｒ^２１は、置換アルキル、または置換アリールである；Ｒ^２２は、アルキルである；Ｒ^２３は、Ｏ、または−ＮＨＲ^２６である；Ｒ^２６は、水素、アルキル、または−Ｃ（＝Ｏ）ＮＨＲ^２７である；Ｒ^２７は、アルキルである；そしてＲ^２４は、置換アリールである。

When the bond represented by is a double bond, it does not exist. In another specific embodiment of the invention, R ²⁰ is hydrogen; R ²¹ is substituted alkyl, or substituted aryl; R ²² is alkyl; R ²³ is O, or —NHR ²⁶ R ²⁶ is hydrogen, alkyl, or —C (═O) NHR ²⁷ ; R ²⁷ is alkyl; and R ²⁴ is substituted aryl.

  In another specific embodiment, the present invention provides a compound comprising at least one phosphonate and a substructure of formula II, III or IV, or a pharmaceutically acceptable salt thereof:

別の特定の実施態様では、本発明は、式１〜４のいずれかの化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another specific embodiment, the invention provides a compound of any of formulas 1-4, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；そして
Ｒ^２１は、置換アルキルまたは置換アリールである。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and R ²¹ is substituted alkyl or substituted aryl.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 101, or a pharmaceutically acceptable salt thereof:

ここで：Ｒ^２９は、水素、アルキル、または−Ｃ（＝Ｏ）Ｒ^３６である；
Ｒ^３０は、水素または置換アルキルである；そして
Ｒ^３１およびＲ^３２は、別個に、水素、アルキル、または置換アリールである；あるいはＲ^３１およびＲ^３２は、それらが結合する窒素原子と一緒になって、置換または非置換複素環を形成するである；
Ｒ^３３は、−Ｏ−、−ＮＲ^３５−または存在しない；
Ｒ^３４は、−Ｏ−または存在しない；
Ｒ^３５は、水素またはアルキルである；そして
Ｒ^３６は、水素、アルキル、アルケニル、またはアルキニルである。

Where: R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl; and R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² are taken together with the nitrogen atom to which they are attached. Forming a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl; and R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl.

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 101, or a pharmaceutically acceptable salt thereof, wherein R ²⁹ is- C (═O) R ³⁶ ; R ³⁰ is alkyl substituted with —CHR ³⁷ R ³⁸ or —NR ³⁷ R ³⁸ ; R ³¹ and R ³² are independently hydrogen or substituted aryl Or R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted heterocycle, wherein the heterocycle is substituted with hydrogen or alkyl; R ³³ is- NR ³⁵ - ^{a; R 34} is ^{-O-; R 35} is ^{hydrogen; R 36} is alkenyl; and each ^{R 37} and ^{R 38,} independently, hydrogen, alkyl or substituted, Is alkyl ; Or ^NR 37 ^{R 38} form a substituted or unsubstituted heterocyclic ring.

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 101, or a pharmaceutically acceptable salt thereof, wherein: —NR ³¹ R ³² Forms a substituted piperazyl ring having the formula:

ここで、Ｌ^３は、−Ｃ（＝Ｏ）ＮＨ−である；そしてＲ^６７は、水素、置換アルキルまたは置換アリールである。

Where L ³ is —C (═O) NH—; and R ⁶⁷ is hydrogen, substituted alkyl or substituted aryl.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula V or VI, or a pharmaceutically acceptable salt thereof:

別の特定の実施態様では、本発明は、少なくとも１個のホスホネートと式ＶＩＩの下部構造とを含む化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula VII, or a pharmaceutically acceptable salt thereof:

ここで、Ｒ^６７は、置換アリールである。

Here, R ⁶⁷ is substituted aryl.

  In another specific embodiment, the invention provides a compound of formula 101, or a pharmaceutically acceptable salt thereof, which is a compound of formula 5, 6 or 7:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
ここで、Ｒ^２９〜Ｒ^３４は、本明細書中で規定した値のいずれかである。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Here, R ^{29 to} R ³⁴ are any of the values defined in this specification.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 102, or a pharmaceutically acceptable salt thereof;

別の特定の実施態様では、本発明は、少なくとも１個のホスホネートと式ＶＩＩＩの下部構造とを含む化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula VIII, or a pharmaceutically acceptable salt thereof:

ここで、各Ｒ^３９およびＲ^４０は、別個に、水素、フッ素、塩素、臭素またはヨウ素である；そしてｎａおよびｍａは、それぞれ別個に、１、２、３または４である；
別の特定の実施態様では、本発明は、少なくとも１個のホスホネートと式ＩＸの下部構造とを含む化合物、またはそれらの薬学的に受容可能な塩を提供する：

Where each R ³⁹ and R ⁴⁰ is independently hydrogen, fluorine, chlorine, bromine or iodine; and na and ma are each independently 1, 2, 3 or 4;
In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula IX, or a pharmaceutically acceptable salt thereof:

ここで、Ｒ^４１、Ｒ^４２、Ｒ^４３およびＲ^４４は、別個に、水素、フッ素、塩素、臭素またはヨウ素である。Ｒ^４１、Ｒ^４２およびＲ^４３についての特定の値は、フッ素である；そしてＲ^４４についての特定の値は、ヨウ素である。

Here, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are each independently hydrogen, fluorine, chlorine, bromine or iodine. A specific value for R ⁴¹ , R ⁴² and R ⁴³ is fluorine; and a specific value for R ⁴⁴ is iodine.

  In another specific embodiment, the invention provides a compound of any one of formulas 8-10, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 103 or formula 104, or a pharmaceutically acceptable salt thereof.

別の特定の実施態様では、本発明は、少なくとも１個のホスホネートと式Ｘの下部構造とを含む化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula X, or a pharmaceutically acceptable salt thereof:

ここで、Ｒ^４５は、水素、−ＮＨ−（Ｃ_６〜Ｃ_２０）アリールまたは−ＮＨ−置換（Ｃ_６〜Ｃ_２０）アリールである；Ａ_ａは、炭素環または複素環である；そしてＲ^４６は、置換複素環である。

Where R ⁴⁵ is hydrogen, —NH— (C ₆ -C ₂₀ ) aryl or —NH-substituted (C ₆ -C ₂₀ ) aryl; A _a is a carbocyclic or heterocyclic ring; and R ⁴⁶ is a substituted heterocyclic ring.

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula X, or a pharmaceutically acceptable salt thereof, wherein A _a is substituted R ⁴⁶ is piperazyl substituted with alkyl or substituted alkyl; and R ⁴⁵ is —NH— (substituted aryl).

  In another embodiment, this invention provides a compound comprising the substructure of formula 103 or formula 104 and at least one phosphonate group, or a pharmaceutically acceptable salt thereof; Including substructure:

ここで、Ｒ^４７およびＲ^４８は、別個に、水素または（Ｃ_１〜Ｃ_４）アルキルであるか、あるいはＲ^４７およびＲ^４８は、それらが結合する窒素原子と一緒になって、置換または非置換複素環を形成する。

Where R ⁴⁷ and R ⁴⁸ are independently hydrogen or (C ₁ -C ₄ ) alkyl, or R ⁴⁷ and R ⁴⁸ together with the nitrogen atom to which they are attached are substituted or non- Form a substituted heterocycle.

  In another embodiment, this invention provides a compound of any one of formulas 11-14, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子のアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

R ^y is independently H, W ³ , R ² or a protecting group;
R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 105, or a pharmaceutically acceptable salt thereof:

別の特定の実施態様では、本発明は、少なくとも１個のホスホネートと式ＸＩ、ＸＩＩまたはＸＩＩＩの下部構造とを含む化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula XI, XII, or XIII, or a pharmaceutically acceptable salt thereof:

ここで：
Ｒ^４９は、水素、−（Ｃ_６〜Ｃ_２０）アリールまたは−（Ｃ_６〜Ｃ_２０）置換アリールである；
Ｒ^５０は、水素、置換アルキル、または−Ｃ（＝Ｏ）ＮＲ^５１Ｒ^５２である；
Ｒ^５１およびＲ^５２は、別個に、水素、アルキル、または置換アルキルである；そして
Ｒ^５５は、結合またはアルキレンである。

here:
R ⁴⁹ is hydrogen, — (C ₆ -C ₂₀ ) aryl or — (C ₆ -C ₂₀ ) -substituted aryl;
R ⁵⁰ is hydrogen, substituted alkyl, or —C (═O) NR ⁵¹ R ⁵² ;
R ⁵¹ and R ⁵² are independently hydrogen, alkyl, or substituted alkyl; and R ⁵⁵ is a bond or alkylene.

In another specific embodiment, the invention provides a compound comprising a substructure of formula XI, XII or XIII and at least one phosphonate group, or a pharmaceutically acceptable salt thereof, wherein: R ⁴⁹ is substituted aryl; R ⁵⁰ is —C (═O) NR ⁵¹ R ⁵² ; R ⁵¹ is hydrogen; R ⁵² is —NR ⁵³ R ⁵⁴ (C ₁ -C ₆ ). R ⁵³ and R ⁵⁴ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle; and R ⁵⁵ is methylene.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 105, or a pharmaceutically acceptable salt thereof; Including structure:

別の実施態様では、本発明は、式１５または１６の化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another embodiment, this invention provides a compound of formula 15 or 16, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子のアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

R ^y is independently H, W ³ , R ² or a protecting group;
R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula 106, or a pharmaceutically acceptable salt thereof:

ここで：Ｒ^５６は、−Ｎ−、または−ＣＲ^５７−である；そして
Ｒ^５７は、水素またはアルキルである。

Where: R ⁵⁶ is —N— or —CR ⁵⁷ —; and R ⁵⁷ is hydrogen or alkyl.

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula XIV, or a pharmaceutically acceptable salt thereof:

ここで：Ｒ^５６は、−Ｎ−、または−ＣＲ^５７−である；
Ｒ^５７は、水素またはアルキルである；
Ｒ^５８は、水素、ハロ、アルキル、縮合炭素環または縮合複素環である；
Ｒ^５９は、＝ＣＲ^６４−または＝Ｎ−ＮＲ^６４−である；
Ｒ^６０は、フェニルまたはピロリルである；
各Ｒ^６１は、別個に、アルキル、または極性基である；
Ｒ^６４は、別個に、水素またはアルキルである；そして
ｎｂは、０、１、２または３である。

Where: R ⁵⁶ is —N— or —CR ⁵⁷ —;
R ⁵⁷ is hydrogen or alkyl;
R ⁵⁸ is hydrogen, halo, alkyl, fused carbocycle or fused heterocycle;
And R ^59, = ^{CR 64} - or = ^{N-NR 64} - is;
R ⁶⁰ is phenyl or pyrrolyl;
Each R ⁶¹ is independently an alkyl or polar group;
R ⁶⁴ is independently hydrogen or alkyl; and nb is 0, 1, 2, or 3.

In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of formula XIV, or a pharmaceutically acceptable salt thereof, wherein: R ^{56 is-} R ⁵⁸ is hydrogen, halo, or a fused carbocycle or fused heterocycle; R ⁵⁹ is ═CH— or ═N—NH—; R ⁶⁰ is phenyl. Each R ⁶¹ is independently alkyl, —C (═O) NR ⁶² R ⁶³ ; or —S (═O) ₂ NR ⁶² R ⁶³ ; and each R ⁶² and R ⁶³ is Separately, hydrogen, alkyl, or substituted alkyl.

  In another embodiment, the present invention provides a compound comprising at least one phosphonate and a substructure of formula XV, XVI or VII, or a pharmaceutically acceptable salt thereof:

別の実施態様では、本発明は、式１７、１８または１９の化合物、またはそれらの薬学的に受容可能な塩を提供する：

In another embodiment, this invention provides a compound of formula 17, 18, or 19, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；そして
Ｒ^５８は、水素またはハロである。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is a 0,1,2,3,4,5,6,7,8,9,10,11 or 12; and R ⁵⁸ is hydrogen or halo.

  In another embodiment, this invention provides a compound of any one of formulas 20-24, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｒ^６５は、水素、アルキルまたはハロである；そして
Ｒ^６６は、炭素環、複素環、置換炭素環、または置換複素環であり、そして１個またはそれ以上のＡ^０で置換されている。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ⁶⁵ is hydrogen, alkyl or halo; and R ⁶⁶ is a carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A ⁰ .

  In another specific embodiment, the invention provides a compound comprising at least one phosphonate and a substructure of any one of formulas II-XVII, or a pharmaceutically acceptable salt thereof:

ここで：
各Ｒ^３９およびＲ^４０は、別個に、水素、フッ素、塩素、臭素またはヨウ素である；
ｎａおよびｍａは、それぞれ別個に、１、２、３または４である；
Ｒ^４１、Ｒ^４２、Ｒ^４３およびＲ^４４は、別個に、水素、フッ素、塩素、臭素またはヨウ素である；
Ｒ^４５は、水素、−ＮＨ−（Ｃ_６〜Ｃ_２０）アリールまたは−ＮＨ−置換（Ｃ_６〜Ｃ_２０）アリールである；
Ａ_ａは、炭素環または複素環である；
Ｒ^４６は、置換複素環である；
Ｒ^４９は、水素、−（Ｃ_６〜Ｃ_２０）アリールまたは−（Ｃ_６〜Ｃ_２０）置換アリールである；
Ｒ^５０は、水素、置換アルキル、または−Ｃ（＝Ｏ）ＮＲ^５１Ｒ^５２である；
Ｒ^５１およびＲ^５２は、別個に、水素、アルキル、または置換アルキルである；
Ｒ^５５は、結合またはアルキレンである；
Ｒ^５６は、−Ｎ−、または−ＣＲ^５７−である；
Ｒ^５７は、水素またはアルキルである；
Ｒ^５８は、水素、ハロ、アルキル、縮合炭素環または縮合複素環である；
Ｒ^５９は、＝ＣＲ^６４−または＝Ｎ−ＮＲ^６４−である；
Ｒ^６０は、フェニルまたはピロリルである；
各Ｒ^６１は、別個に、アルキル、または極性基である；；
各Ｒ^６４は、別個に、水素またはアルキルである；；
Ｒ^６７は、置換アリールである；そして
ｎｂは、０、１、２または３である。

here:
Each R ³⁹ and R ⁴⁰ is independently hydrogen, fluorine, chlorine, bromine or iodine;
na and ma are each independently 1, 2, 3 or 4;
R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently hydrogen, fluorine, chlorine, bromine or iodine;
R ⁴⁵ is hydrogen, —NH— (C ₆ -C ₂₀ ) aryl or —NH-substituted (C ₆ -C ₂₀ ) aryl;
A _a is a carbocyclic or heterocyclic ring;
R ⁴⁶ is a substituted heterocycle;
R ⁴⁹ is hydrogen, — (C ₆ -C ₂₀ ) aryl or — (C ₆ -C ₂₀ ) -substituted aryl;
R ⁵⁰ is hydrogen, substituted alkyl, or —C (═O) NR ⁵¹ R ⁵² ;
R ⁵¹ and R ⁵² are independently hydrogen, alkyl, or substituted alkyl;
R ⁵⁵ is a bond or alkylene;
R ⁵⁶ is —N— or —CR ⁵⁷ —;
R ⁵⁷ is hydrogen or alkyl;
R ⁵⁸ is hydrogen, halo, alkyl, fused carbocycle or fused heterocycle;
And R ^59, = ^{CR 64} - or = ^{N-NR 64} - is;
R ⁶⁰ is phenyl or pyrrolyl;
Each R ⁶¹ is independently an alkyl or polar group;
Each R ⁶⁴ is independently hydrogen or alkyl;
R ⁶⁷ is substituted aryl; and nb is 0, 1, 2, or 3.

  In another embodiment, this invention provides a compound comprising a substructure of any one of formulas 1-24, or a pharmaceutically acceptable salt thereof:

ここで：
Ａ^０は、Ａ^１である；
Ａ^１は、以下である：

here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、または−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基、または次式である：

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されているとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^ｘ、−Ｓ（Ｏ）（ＯＲ^ｘ）、−Ｓ（Ｏ）_２（ＯＲ^ｘ）、−ＯＣ（Ｙ^１）Ｒ^ｘ、−ＯＣ（Ｙ^１）ＯＲ^ｘ、−ＯＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−ＳＣ（Ｙ^１）Ｒ^ｘ、−ＳＣ（Ｙ^１）ＯＲ^ｘ、−ＳＣ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）Ｒ^ｘ、−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）ＯＲ^ｘ、または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子のアルキル、２個〜１８個の炭素原子のアルケニル、または２個〜１８個の炭素原子のアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５、または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｒ^２１は、置換アルキルまたは置換アリールである；
Ｒ^２９は、水素、アルキル、または−Ｃ（＝Ｏ）Ｒ^３６である；
Ｒ^３０は、水素または置換アルキルである；
Ｒ^３１およびＲ^３２は、別個に、水素、アルキル、または置換アリールである；あるいはＲ^３１およびＲ^３２は、それらが結合する窒素原子と一緒になって、置換または非置換複素環を形成する；
Ｒ^３３は、−Ｏ−、−ＮＲ^３５−または存在しない；
Ｒ^３４は、−Ｏ−または存在しない；
Ｒ^３５は、水素またはアルキルである；
Ｒ^３６は、水素、アルキル、アルケニル、またはアルキニルである；
Ｒ^５８は、水素またはハロである；
Ｒ^６５は、水素、アルキルまたはハロである；そして
Ｒ^６６は、炭素環、複素環、置換炭素環、または置換複素環であり、そして１個またはそれ以上のＡ^０で置換されている。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ²¹ is substituted alkyl or substituted aryl;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl;
R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁸ is hydrogen or halo;
R ⁶⁵ is hydrogen, alkyl or halo; and R ⁶⁶ is a carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A ⁰ .

In one particular embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

そしてＷ^５ａは、炭素環または複素環であり、ここで、Ｗ^５ａは、別個に、０個または１個のＲ^２基で置換されている。Ｍ１２ａについての特定の値は、１である。

W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups. A specific value for M12a is 1.

In another specific embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

本発明の別の特定の実施態様では、Ａ^１は、次式である：

In another specific embodiment of the invention, A ¹ is:

そしてＷ^５ａは、炭素環であり、該炭素環は、別個に、０個または１個のＲ^２基で置換されている。

And W ^5a is a carbocycle, which is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the invention, A ¹ is:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention, A ¹ is:

そしてＷ^５ａは、炭素環であり、該炭素環は、別個に、０個または１個のＲ^２基で置換されている。

And W ^5a is a carbocycle, which is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the invention, A ¹ is:

ここで、Ｗ^５ａは、炭素環または複素環であり、ここで、Ｗ^５ａは、別個に、０個または１個のＲ^２基で置換されている。

Here, W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the invention, A ¹ is:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a particular embodiment of the invention, A ³ is:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^ｘ）またはＳである。

Where Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である。

Here, Y ^2b is O or N (R ^x ).

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

  In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ｗ^５は、炭素環である。

In another specific embodiment of the invention W ⁵ is a carbocycle.

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ｗ^５は、フェニルである。

In another specific embodiment of the invention W ⁵ is phenyl.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^ｘ）またはＳである。

Where Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である。

Here, Y ^2b is O or N (R ^x ).

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R ¹ is H.

In another specific embodiment of the invention A ³ is of the formula:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

Here, the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^２）またはＳである。

Wherein Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

Wherein Y ^1a is O or S; Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；Ｙ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^1a is O or S; Y ^2b is O or N (R ² ); Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である。

Here, Y ^2b is O or N (R ² ).

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

本発明の別の特定の実施態様では、Ａ^３は、次式である：

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^２）またはＳである。

Wherein Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

Wherein Y ^1a is O or S; Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；Ｙ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^1a is O or S; Y ^2b is O or N (R ² ); Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である。

Here, Y ^2b is O or N (R ² ).

In another specific embodiment of the invention A ³ is of the formula:

ここで：Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

Where: Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A ³ is of the formula:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

Here, the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the invention A ³ is of the formula:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

Here, the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the invention A ³ is of the formula:

本発明の特定の実施態様では、Ａ^０は、次式である：

In a particular embodiment of the invention, A ⁰ is:

ここで、各Ｒは、別個に、（Ｃ_１〜Ｃ_６）アルキルである。

Here, each R is independently (C ₁ -C ₆ ) alkyl.

In certain embodiments of the invention, R ^x is independently H, R ¹ , W ³ , a protecting group, or the following formula:

ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子のアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、あるいは炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素の環を形成し、該環は、０個〜３個のＲ^３基で置換され得る。

here:
R ^y is independently H, W ³ , R ² or a protecting group;
R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups, or with carbon atoms Together, the two R ² groups form a 3-8 carbon ring, which can be substituted with 0-3 R ³ groups.

In a particular embodiment of the invention, R ^x is:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

Where Y ^1a is O or S; and Y ^2c is O, N (R ^y ) or S.

In a particular embodiment of the invention, R ^x is:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である。

Where Y ^1a is O or S; and Y ^2d is O or N (R ^y ).

In a particular embodiment of the invention, R ^x is:

本発明の特定の実施態様では、Ｒ^ｙは、水素または１個〜１０個の炭素のアルキルである。

In certain embodiments of the invention, R ^y is hydrogen or alkyl of 1 to 10 carbons.

In a particular embodiment of the invention, R ^x is:

本発明の特定の実施態様では、Ｒ^ｘは、次式である：

In a particular embodiment of the invention, R ^x is:

本発明の特定の実施態様では、Ｒ^ｘは、次式である：

In a particular embodiment of the invention, R ^x is:

本発明の特定の実施態様では、Ｙ^１は、ＯまたはＳである。

In a particular embodiment of the invention Y ¹ is O or S.

In a particular embodiment of the invention Y ² is O, N (R ^y ) or S.

In one particular embodiment of the invention, R ^x is a group of the formula:

ここで：
ｍ１ａ、ｍ１ｂ、ｍ１ｃ、ｍ１ｄおよびｍ１ｅは、別個に、０または１である；
ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｒ^ｙは、Ｈ、Ｗ^３、Ｒ^２または保護基である；
但し：
もし、ｍ１ａ、ｍ１２ｃおよびｍ１ｄが０なら、ｍ１ｂ、ｍ１ｃおよびｍ１ｅは、０である；
もし、ｍ１ａおよびｍ１２ｃが０であり、そしてｍ１ｄが０ではないなら、ｍ１ｂおよびｍ１ｃは、０である；
もし、ｍ１ａおよびｍ１ｄが０であり、ｍ１２ｃが０ではないなら、ｍ１ｂと、ｍ１ｃおよびｍ１ｅの少なくとも１個とは、０である；
もし、ｍ１ａが０であり、そしてｍ１２ｃおよびｍ１ｄが０ではないなら、ｍ１ｂは、０である；
もし、ｍ１２ｃおよびｍ１ｄが０であり、そしてｍ１ａが０ではないなら、ｍ１ｂ、ｍ１ｃおよびｍ１ｅの少なくとも２個は、０である；
もし、ｍ１２ｃが０であり、そしてｍ１ａおよびｍ１ｄが０ではないなら、ｍ１ｂおよびｍ１ｃの少なくとも１個は、０である；そして
もし、ｍ１ｄが０であり、そしてｍ１ａおよびｍ１２ｃが０ではないなら、ｍ１ｃおよびｍ１ｅの少なくとも１個は、０である。

here:
m1a, m1b, m1c, m1d and m1e are independently 0 or 1;
m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ^y is H, W ³ , R ² or a protecting group;
However:
If m1a, m12c and m1d are 0, m1b, m1c and m1e are 0;
If m1a and m12c are 0 and m1d is not 0, m1b and m1c are 0;
If m1a and m1d are 0 and m12c is not 0, m1b and at least one of m1c and m1e are 0;
If m1a is 0 and m12c and m1d are not 0, m1b is 0;
If m12c and m1d are 0 and m1a is not 0, at least two of m1b, m1c and m1e are 0;
If m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1c is 0; and if m1d is 0 and m1a and m12c are not 0, At least one of m1c and m1e is 0.

In the compounds of the present invention, the W ⁵ carbocycle and the W ⁵ heterocycle can be independently substituted with 0 to 3 R ² groups. W ⁵ can be a saturated, unsaturated or aromatic ring, including mono- or bicyclic carbocycles or heterocycles. W ⁵ can have 3 to 10 ring atoms (eg, 3 to 7 ring atoms). These W ⁵ rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, and saturated when containing 5 ring atoms. Monounsaturated or diunsaturated, and when containing 6 ring atoms, is saturated, monounsaturated, diunsaturated or aromatic.

W ⁵ heterocycle has 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms (which are selected from N, O, P and S)) Having a single ring or 2 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms, which are selected from N, O, P and S) It can be a ring. W ⁵ heterocycle is a ring of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms, which are selected from N, O, P and S) Or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms (which are selected from N, O, P and S)) Can have. W ⁵ heterobicycles contain 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms, which are selected from N, O and S) Having these (arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] system); or 9-10 ring atoms (8- Having 9 carbon atoms and 1 to 2 heteroatoms (which are selected from N and S), which are arranged as a bicyclo [5,6] or [6,6] system ) This W ⁵ heterocycle can be attached to Y ² via a carbon, nitrogen, sulfur or other atom by a stable covalent bond.

W ⁵ heterocycles include, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl and pyrrolyl. . W ⁵ also includes, but is not limited to, for example:

Ｗ^５炭素環および複素環は、別個に、０個〜３個のＲ^２基で置換され得る。例えば、置換Ｗ^５炭素環には、以下が挙げられる：

The W ⁵ carbocycle and the heterocycle can be independently substituted with 0 to 3 R ² groups. For example, substituted W ⁵ carbocycles include the following:

置換フェニル炭素環の例には、以下が挙げられる：

Examples of substituted phenyl carbocycles include the following:

（連結基およびリンカー）
本発明は、直接（例えば、共有結合を介して）または連結基（すなわち、リンカー）を介して、いずれかで、１個またはそれ以上のホスホネート基に連結されたキナーゼ阻害化合物を含有する抱合体を提供する。このリンカーの性質は、このホスホネート含有化合物が治療薬として機能する性能を妨害しないという条件で、重要ではない。このホスホネートまたはリンカーは、この化合物の水素または他の部分を除去してホスホネートまたはリンカーの結合のための開放原子価を提供することにより、その化合物上の任意の実行可能な位置で、この化合物に連結できる。

(Linking group and linker)
The present invention contemplates conjugates containing a kinase inhibitor compound linked to one or more phosphonate groups, either directly (eg, via a covalent bond) or via a linking group (ie, a linker). I will provide a. The nature of the linker is not critical provided that the phosphonate-containing compound does not interfere with its ability to function as a therapeutic agent. The phosphonate or linker can be attached to the compound at any feasible position on the compound by removing the hydrogen or other moiety of the compound to provide an open valence for attachment of the phosphonate or linker. Can be linked.

In one embodiment of the present invention, the linking group or linker (which can be represented as “L”) can be attached to all or part of the A ⁰ , A ¹ or W ³ groups described herein. Can be included.

  In another embodiment of the invention the linking group or linker has a molecular weight of about 20 daltons to about 400 daltons.

  In another embodiment of the invention the linking group or linker has a length of about 5 angstroms to about 300 angstroms.

  In another embodiment of the invention the linking group or linker separates DRUG and P (= Y1) residues by a length of about 5 angstroms to about 200 angstroms (inclusive).

In another embodiment of the invention the linking group or linker is a divalent branched or unbranched saturated or unsaturated hydrocarbon chain, wherein the hydrocarbon chain contains 2 to 25 carbon atoms. Wherein one or more of the carbon atoms (eg, 1, 2, 3 or 4) is optionally replaced with (—O—), wherein The chain is optionally substituted on the carbon with one or more (eg, 1, 2, 3 or 4) substituents, wherein the substituents are (C ₁ -C _{6) alkoxy, (C} 3 ~C _{6) cycloalkyl, (C} 1 ~C _{6) alkanoyl, (C} 1 ~C _{6) alkanoyloxy, (C} 1 ~C _{6) alkoxycarbonyl, (C} 1 -C ₆₎ alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (= O) Carboxy, aryl, aryloxy, heteroaryl and heteroaryloxy.

In another embodiment of the present invention the linking group or linker is of the formula W-A, wherein, A _{is, (C} 1 _{~C 24) alkyl, (C} 2 _{~C 24)} alkenyl, _{(C 2} -C _{24) alkynyl, (C} 3 ~C _{8) cycloalkyl, (C} 6 _{~C 10)} aryl, or a combination thereof, wherein, W is, -N (R) C (= O) -, - C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R) -, - C (= O) - or a direct bond; wherein each R is independently, H or _(C 1 _{~C 6)} alkyl.

  In another embodiment of the invention the linking group or linker is a divalent radical formed from a peptide.

  In another embodiment of the invention the linking group or linker is a divalent radical formed from an amino acid.

  In another embodiment of the invention, the linking group or linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L. A divalent radical formed from threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is of the formula W— (CH ₂ ) _n , wherein n is between about 1 and about 10; and W is —N ( R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O )-, -S (O) _2- , -C (= O)-, -N (R)-, -N (R) C = N (R) -N (R)-, -C (R) = N (R)-, -S (O) _M2- N (R)-, -N (R) -S (O) _M2-, or a direct bond; where each R is independently H or ( C ₁ -C ₆₎ alkyl.

  In another embodiment of the invention the linking group or linker is methylene, ethylene or propylene.

  In another embodiment of the invention the linking group or linker is attached to the phosphonate group via a carbon atom of the linker.

(Intracellular targeting)
The phosphonate groups of the compounds of the invention can be cleaved stepwise in vivo after they reach the desired desired site (ie, inside the cell). One mechanism of action inside the cell may involve an initial cleavage (eg, by an esterase) to provide a negatively charged “locked-in” intermediate. Thus, cleavage of the terminal ester grouped in the compounds of the present invention provides an unstable intermediate that releases a negatively charged “fixed” intermediate.

  After passing inside the cell, intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound can result in intracellular accumulation of the cleaved or modified compound by a “capture” mechanism. The cleaved or modified compound then has a charge that reduces the rate at which the cleaved or modified compound can escape from the cell compared to the rate at which the compound enters as a phosphonate prodrug. It can be “fixed” in the cell by a significant change in polarity, or other physical property. Other mechanisms by which the therapeutic effect is achieved may also be operable. Enzymes capable of enzyme activation including the phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase, and phosphatase.

  From the foregoing it is clear that many different drugs can be derivatized in accordance with the present invention. A number of such agents are specifically mentioned herein. However, it should be understood that the lineage of drugs for derivatization according to the present invention and the discussion of their particular members are merely exemplary and are not to be construed as exhaustive.

(Kinase inhibitor compound)
The compounds of the present invention include those having kinase inhibitory activity. The compounds of the invention comprise one or more (eg, 1, 2, 3 or 4) phosphonate groups, which can be prodrug moieties.

  The term “kinase inhibitory compound” includes compounds that inhibit the activity of at least one kinase. In particular, these compounds include PD 173955, PD 166326, and PD 173074, as well as Iressa, Tarceva, MLN-518, ZD-6474 and Canertiv; PD-0325901; BMS-354825; CP-547, 632; Semaxanib, SU-11248, and GW 9499.

  Typically, the compounds of the present invention have a molecular weight of about 400 amu to about 10,000 amu; in certain embodiments of the present invention, the compounds have a molecular weight of less than about 5000 amu; In embodiments, the compound has a molecular weight of less than about 2500 amu; in other specific embodiments of the invention, the compound has a molecular weight of less than about 1000 amu; in other specific embodiments of the invention, the compound is In other specific embodiments of the invention, the compound has a molecular weight of less than about 600 amu; and in other specific embodiments of the invention, the compound has a molecular weight of less than about 600 amu. It has a molecular weight and a molecular weight higher than about 400 amu.

  The compounds of the present invention also typically have a log D (polarity) of less than about 5. In one embodiment, the present invention provides a compound having a log D of less than about 4; in other embodiments, the present invention provides a compound having a log D of less than about 3; The invention provides compounds with a log D higher than about −5; in other embodiments, the invention provides compounds with a log D higher than about −3; and in other embodiments, the invention provides: Compounds having a log D greater than about 0 and less than about 3 are provided.

Substituents selected within the compounds of the invention are present to a recursive extent. In this context, “recursive substituent” means that a substituent may describe other instances of itself. Due to the recursive nature of such substituents, in theory there can be many in any given embodiment. For example, R ^x contains an R ^y substituent. R ^y can be R ² , which in turn can be R ³ . If R ³ is selected to be R ^3c , the second case of R ^x can be selected. One skilled in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the target compound. Such properties include, but are not limited to, physical properties (eg, molecular weight, solubility or log P), application properties (eg, activity against the target of interest) and practical properties (eg, ease of synthesis). It is done.

By way of example and not limitation, in certain embodiments, W ³ , R ^y and R ³ are all recursive substituents. Typically, each of these is separately, in certain embodiments, 20 times, 19 times, 18 times, 17 times, 16 times, 15 times, 14 times, 13 times, 12 times, 11 times, 10 times. 9 times, 8 times, 7 times, 6 times, 5 times, 4 times, 3 times, 2 times, 1 time or 0 times. More typically, each of these may be present separately, and in certain embodiments, 12 or fewer times. More typically, in certain embodiments, W ³ is present 0 to 8 times, R ^y is present 0 to 6 times, and R ³ is present 0 to 10 times. Even more typically, in certain embodiments, W ³ is present 0 to 6 times, R ^y is present 0 to 6 times, and R ³ is present 0 to 8 times.

  Recursive substituents are an intended aspect of the invention. Those skilled in the art of medicinal chemistry understand the versatility of such substituents. To the extent that recursive substituents are present in embodiments of the present invention, the total number is determined as indicated above.

Whenever a compound described herein is substituted with more than one of the same designated groups (eg, “R ¹ ” or “R ^6a ”), the groups can be the same or different, ie, each group It can be seen that are selected separately. The wavy line indicates the site of covalent bonding to an adjacent group, moiety or atom.

  In one embodiment of the invention, the compound is in an isolated and purified state. In general, the term “isolated and purified” means that the compound is substantially free of biological material (eg, station, tissue, cell, etc.). In one particular embodiment of the invention, the term means that the compound or conjugate of the invention does not contain at least about 50% by weight of biological material; in another embodiment, the term Means that the compound or conjugate is free of at least about 75% biological material; in other embodiments, the term means that the compound or conjugate of the invention is free of at least about 90% biological material. Means; in other embodiments, the term means that the compound or conjugate of the invention is free of at least about 98% by weight of biological material; in other embodiments, the term means a compound of the invention Or it means that the conjugate does not contain at least about 99% by weight of biological material. In another specific embodiment, the present invention provides a compound or conjugate of the present invention that is synthetically prepared (eg, semi-vivo).

  In one embodiment of the invention, the compound is not an anti-inflammatory compound; in other embodiments, the compound is not an anti-infective; in other embodiments, the compound is an immune-mediated condition. In other embodiments, the compound is not active against metabolic diseases; in other embodiments, the compound is not an antiviral agent; in other embodiments, the compound Is not a nucleoside; in other embodiments, the compound is not an IMPDH inhibitor; in other embodiments, the compound is not an antimetabolite; in other embodiments, the compound is a PNP inhibitor In other embodiments, the compound is a serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin dependent kinase, Flt3 tyrosine kinase. Inhibiting MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, or EGF receptor tyrosine kinase; , Batalanib, albocinib, CEP-701, GLEEVEC, midostaurine, MLN-518, PD-184352, dramapimod, BAY-43-9006, or CP-690,550 (one or more of these) Is substituted with phosphonates).

(Cell accumulation)
In one embodiment, the present invention provides compounds that can accumulate in human PBMC (peripheral blood mononuclear cells). PBMC refers to blood cells having round lymphocytes and monocytes. Physiologically, PBMC is an important component of the mechanism for infection. PBMCs can be isolated from heparinized whole blood or buffy coats of normal healthy donors by standard density gradient centrifugation, collected from the interface, washed (eg, phosphate buffered saline) And can be stored in freezing medium. PBMC can be cultured in multi-well plates. At various times in culture, the supernatant can either be removed for evaluation or the cells can be collected and analyzed (Smith R. et al. (2003) Blood 102 (7): 2532- 2540). The compounds of this embodiment may further contain a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug may have the A ³ structure described herein.

  Typically, a compound of the present invention has an improved intracellular half-life of the compound or an intracellular metabolite of the compound in human PBMC when compared to a phosphonate or an analog of a compound without a phosphonate prodrug. Show. Typically, the half-life is at least about 50%, more typically in the range of at least 50% to 100%, even more typically at least about 100%, more typically still less than about 100%. Big and improved.

  In one embodiment of the invention, the intracellular half-life of a metabolite of the compound in human PBMC is improved when compared to a phosphonate or an analog of a compound without a phosphonate prodrug. In such embodiments, the metabolite can be produced intracellularly, eg, produced in human PBMC. The metabolite may be the product of phosphonate prodrug cleavage within human PBMC. The phosphonate prodrug can be cleaved to form at least one negatively charged metabolite at physiological pH. This optional phosphonate prodrug containing phosphonate can be enzymatically cleaved in human PBMC to form a phosphonate having at least one active hydrogen atom in the P-OH form.

(Stereoisomers)
The compounds of the present invention may have chiral centers (eg, chiral carbon or phosphorus atoms). Thus, the compounds of the present invention include all stereoisomers (including enantiomers, diastereomers and atropisomers). In addition, the compounds of the present invention include enhanced or resolved enantiomers at any or all asymmetric chiral atoms. In other words, the chiral centers apparent from their depiction are provided as their chiral isomers or racemic mixtures. Not only both racemic and diastereomeric mixtures, but also the individual optical isomers isolated or synthesized which are substantially free of their enantiomeric partners or diastereomeric bar toners Is within the range. These racemic mixtures can be obtained by well-known techniques such as separation of diastereomeric salts formed using optically active auxiliary agents (eg acids or bases followed by conversion back to their optically active substances). Are separated into individual substantially optically pure isomers. In most cases, the desired optical isomer is synthesized by a stereospecific reaction starting with the appropriate stereoisomer of the desired starting material.

  The compounds of the invention may also exist as tautomers in certain cases. Although only one delocalized resonance structure can be depicted, all such shapes are considered within the scope of the present invention. For example, ene-amine tautomers can exist in purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all possible tautomeric forms are within the scope of the present invention.

(Salts and hydrates)
The compositions of the present invention may optionally contain salts of the compounds herein (especially pharmaceutically acceptable non-toxic salts (eg, Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺² and Containing Mg ⁺² )). Such salts were derived by incorporating appropriate cations (eg, alkali metal and alkaline earth metal ions or ammonium and quaternary amino ions) and acid anion moieties (typically carboxylic acids). Things. Monovalent salts are preferred if water soluble salts are desired.

Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts thus prepared include salts containing Li ⁺ , Na ⁺ and K ⁺ . A metal salt with low solubility can be precipitated from a solution of a highly soluble salt by adding a suitable metal compound.

In addition, certain organic and inorganic acids (eg, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ or organic sulfonic acids) can be acidified to a base center (typically an amine) or acidic group. Can be formed from the addition. Finally, the compositions herein contain the compounds of the invention in combination with a stoichiometric amount of water, such as zwitterionic forms and hydrates as well as their non-ionized forms. Should be able to understand.

  Also within the scope of the invention are salts of the parent compound with one or more amino acids. Any of the above amino acids (especially naturally occurring amino acids found as protein components) are suitable, but typically the amino acid has a side chain with a base or acid group (eg, lysine). , Arginine or glutamic acid) or having a side chain with a neutral group (eg glycine, serine, threonine, alanine, isoleucine or leucine).

(Methods for inhibiting kinases)
Another aspect of the invention relates to a method of inhibiting the activity of at least one kinase, the method comprising contacting an analyte suspected of containing a kinase with a composition of the invention.

  The compounds of the present invention can act as kinase inhibitors, intermediates for such inhibitors, or have other utilities as described herein. These inhibitors bind to at least one kinase. Compounds that bind kinases can bind to varying degrees of reversibility. Compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, compounds that bind substantially irreversibly are useful as probes for the detection of kinases. Accordingly, the present invention relates to a method for detecting at least one kinase in an analyte suspected of containing a kinase, the method comprising the following steps: labeling an analyte suspected of containing a kinase Treatment with a composition comprising a compound of the invention bound to, and observing the effect of the analyte on the activity of the label. Suitable labels are well known in the diagnostic field and include free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in the usual manner using functional groups (eg, hydroxyl or amino).

  In the context of the present invention, analytes suspected of containing at least one kinase include natural or artificial substances (eg, biological organisms; tissues or cell cultures; biological samples (eg, biomaterial samples ( For example, blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.))); laboratory samples; food, water or air samples; Recombinant cells that synthesize glycoproteins)) and the like. Typically, this specimen is suspected of containing a kinase. The analyte can be contained in any medium including water and organic solvent / water mixtures. Samples include biological organisms (eg, humans) and artificial materials (eg, cell cultures).

  The processing step of the present invention includes the step of adding the composition of the present invention to the specimen, or the step of adding a precursor of the composition to the specimen. This addition step includes any administration method described above.

  If desired, the activity of the kinase after application of the composition can be observed by any method, including direct and indirect methods of detecting kinase activity. Quantitative, qualitative and semi-quantitative methods for determining kinase activity are all considered. Typically, one of the above screening methods is applied, however, any other method (eg, observing the physiological properties of a biological organism) can also be applied.

  Many organisms contain kinases. The compounds of the present invention are useful in the treatment or prevention of diseases associated with kinase activity in animals (eg, mammals (eg, humans)).

  However, in screening for compounds that can inhibit kinases, it should be noted that the results of enzyme assays cannot be correlated with cell culture assays. Cell-based assays should therefore be the primary screening tool.

(Screen for kinase inhibitors)
The compositions of the invention are screened for inhibitory activity against kinases by any of the usual techniques for assessing enzyme activity. In the context of the present invention, typically compositions are first screened for inhibition of kinases in vitro, and compositions exhibiting inhibitory activity are then screened for activity in vivo. Compositions having an in vitro Ki (inhibition constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M, preferably less than about 5 × 10 ⁻⁸ M are used in vitro. It is preferable to do.

  Useful in vitro screens are described, for example, in Bioorg. Med. Chem. Lett. 2001, 11, 2775.

(Pharmaceutical preparation)
The compounds of the invention can be formulated with carriers and excipients, which are selected according to common practice. Tablets contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery other than by oral administration. All formulations optionally contain excipients such as those described in “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents (eg EDTA), carbohydrates (eg dextran), hydroxyalkyl cellulose, hydroxyalkylmethyl cellulose, stearic acid and the like. The pH of these formulations ranges from about 3 to about 11, but is usually about 7-10.

  While it is possible to administer these active ingredients alone, it may be preferred to present them as pharmaceutical formulations. The formulations of the present invention, which are used for both animal and human applications, comprise at least one active ingredient together with one or more acceptable carriers and optionally other therapeutic ingredients. (Which is defined above). These carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically benign to the recipient.

  These formulations include those suitable for the aforementioned administration routes. These formulations may conveniently be presented in unit dosage form and prepared by any of the methods well known in pharmacy. Techniques and formulations can be found at Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, these formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. .

  Formulations of the present invention suitable for oral administration are as discrete units (eg, capsules, cachets or tablets, each containing a predetermined amount of active ingredient); as powders or tablets; aqueous or non-aqueous liquids Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are free-flowing forms of the active ingredient (e.g. powders or granules, which may be combined with binders, lubricants, inert diluents, preservatives, interface, as appropriate) Can be prepared by compressing (mixed with the active agent or dispersant). Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier, which is wet with an inert liquid diluent. These tablets can be coated or imprinted as required and are formulated for slow or controlled release of the active ingredient therefrom, if desired.

  For administration to the eyes or other external tissues (eg mouth and skin), these preparations are preferably applied as topical ointments or creams, which may contain this active ingredient, eg 0.075-20 % By weight (range between 0.1% and 20% with stepwise addition of 0.1% by weight (eg 0.6% by weight, 0.7% by weight, etc.)), preferably 0.2% It is contained in an amount of ˜15% by weight, most preferably 0.5 to 10% by weight. When formulated in an ointment, these active ingredients can be used in either a paraffin base or a water-miscible ointment base. Alternatively, these active ingredients can be formulated in a cream with an oil-in-water cream base.

  If desired, the aqueous phase of the cream base may contain, for example, at least 30% by weight of a polyhydric alcohol (ie, an alcohol having two or more hydroxyl groups (eg, propylene glycol, butane 1,3-diol, mannitol). Sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof)). These topical formulations may desirably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

  The oily phase of the emulsion of the present invention may be composed of known ingredients in a known manner. This phase may simply contain an emulsifier, which is otherwise known as an emission promoter, whereas it desirably comprises at least one emulsifier and a fat or oil or Contains a mixture with both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier (which acts as a stabilizer). It is also preferred to include both oil and fat. These emulsifiers together with or without stabilizers constitute a so-called emulsifying wax, which together with the oil and fat constitutes a so-called emulsifying ointment base, which is An oily dispersed phase is formed.

  Discharge enhancers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween® 60, Span® 80, cetyl stearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monosteare. And sodium lauryl sulfate.

  The selection of an appropriate oil or fat for this formulation is based on achieving the desired appearance characteristics. The cream should preferably be a non-oily, non-staining and washable product with adequate fastness to avoid leakage from tubes or other containers. A straight or branched mono- or dibasic kill ester (e.g., di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, A blend of branched chain esters known as 2-ethylhexyl palmitate or Crodamol CAP) can be used, the last three being the preferred esters. These can be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

  The pharmaceutical formulations of the present invention contain one or more compounds of the present invention, along with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. . The pharmaceutical formulation containing the active agent can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, medicinal drops, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs can be prepared. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can be formulated with sweeteners, dressings to provide palatable formulations. One or more agents may be included, including flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients include, for example, inert diluents (eg, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate); granulating agents and disintegrants (E.g. corn starch or alginic acid); binders (e.g. cellulose, microcrystalline cellulose, starch, gelatin or acacia) and lubricants (e.g. magnesium stearate, stearic acid or talc). These tablets can be coated by known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be used.

  Formulations for oral use include hard gelatin capsules (where the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin), or soft gelatin capsules where the active ingredient Can be provided as water or oil (eg, mixed with peanut oil, liquid paraffin or olive oil).

  The aqueous suspensions of the present invention contain this active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include, for example, suspending agents (eg, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum); dispersants or wetting agents (eg, naturally The resulting phosphatides (eg lecithin), condensation products of alkylene oxides and fatty acids (eg polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (eg heptadecaethyleneoxycetanol), ethylene oxide Products of fatty acids and partial esters derived from hexitol anhydrides, such as polyoxyethylene sorbitol monooleate. The above preservatives (eg, ethyl p-hydroxybenzoate or n-propyl), one or more colorants, one or more flavoring agents, and one or more sweeteners (eg, Sucrose or saccharin).

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (eg, arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (eg, liquid paraffin). This oily suspension may also contain a thickening agent (beeswax, hard paraffin or cetyl alcohol). Sweeteners (eg, listed above) and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by the addition of an antioxidant (eg, ascorbic acid).

  Dispersible powders and granules of the invention suitable for preparing an aqueous suspension by the addition of water contain this active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. To do. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be present.

  The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil (eg, olive oil or peanut oil), a mineral oil (eg, liquid paraffin), or a mixture of these. Suitable emulsifiers include, for example, naturally occurring gums (eg, gum arabic and tragacanth), naturally occurring phosphatides (eg, soy lecithin, esters or partial esters derived from fatty acids and anhydrous hexitol (eg, sorbitan monooles). And a condensation product of the partial ester and ethylene oxide (for example, polyoxyethylene sorbitan monooleate)). The emulsion may also contain sweetening, flavoring and preserving agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative, flavoring or coloring agent.

  The pharmaceutical compositions of the invention may also be in the form of a sterile injectable formulation (eg, a sterile injectable aqueous or oleaginous suspension). This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. This sterile injectable formulation is also a sterile injectable solution or suspension (eg, a solution in 1,3-butanediol) in a nontoxic parenterally acceptable diluent or solvent. Or may be prepared as a lyophilized powder. Among the suitable excipients and solvents that may be used are Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can usually be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used as well for the preparation of injectables.

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation for oral administration to humans may contain about 1-1000 mg of active substance (which is a suitable and convenient amount of carrier substance, which is about 5 to about 95% (by weight) of the total composition. :) which may vary with weight)). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution for intravenous infusion may contain from about 3 to about 500 μg of active ingredient per milliliter of solution so that a suitable volume of infusion can occur at a rate of about 30 mL / hr.

  Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20% by weight, advantageously 0.5 to 10% by weight, in particular about 1.5% by weight. is doing.

  Formulations suitable for topical administration in the mouth include medicinal drops (which contain the active ingredient in a seasoning base (usually sucrose and acacia or tragacanth)); pastilles (which are inert groups) Agents (for example, containing the active ingredient in gelatin and glycerin, or sucrose and acacia) and mouthwashes (which contain the active ingredient in a suitable liquid carrier).

  Formulations for rectal administration may be presented as a suppository with a suitable base (for example containing cocoa butter or salicylate).

  Formulations suitable for intrapulmonary or intranasal administration are, for example, 0.1 to 500 microns (particle sizes with an increased number of microns in the range of between 0.1 and 500 microns (eg,. Particle size in the range of 5, 1, 30, 35 microns, etc.), which can be inhaled by rapid inhalation through the nostrils or through the mouth to reach the alveolar sac To be administered. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or anhydrous powder administration can be prepared according to conventional methods and together with other therapeutic agents (eg, compounds conventionally used in the treatment or prevention of diseases associated with kinase activity) Can be delivered.

  Formulations suitable for intravaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations, which in addition to the active ingredient are suitable as known in the art. Contains a good carrier.

  Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which include antioxidants, buffers, bacteriostats and solutes (this is a recipe for Can be made isotonic with the blood of the ent; and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents.

  These formulations are provided in single-dose or multi-dose containers (eg, sealed ampoules and vials) and stored in a lyophilized state, which is a sterile liquid carrier (eg, for injection) immediately prior to use. It is only necessary to add water). Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage forms are those containing a daily dose or unit daily sub-dose of the active ingredient or an appropriate portion thereof, as previously cited herein.

  In addition to the ingredients specifically mentioned above, the formulations of the present invention may contain other agents common in the art for that type of formulation, for example those suitable for oral administration are flavors It should be understood that it may contain a material.

  The present invention further provides a veterinary composition, which, together with its veterinary carrier, contains at least one active ingredient as defined above.

  A veterinary carrier is a substance useful for the purpose of administering this composition, which is a solid, liquid or gaseous substance, otherwise it is inert or acceptable in the veterinary field and has this activity. Compatible with ingredients. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

  The compounds of the invention are also formulated to provide sustained release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetics or toxicity profile of the active ingredient. Accordingly, the present invention also provides compositions containing one or more compounds of the present invention formulated for sustained release.

  The effective dose of the active ingredient depends at least on the nature of the disease to be treated, toxicity, whether the compound is used prophylactically (low dose), the delivery method, and the pharmaceutical formulation, and the usual dose assessment Determined by the clinician using the study. It can be expected to be from about 0.0001 to about 100 mg / kg body weight / day. Typically, from about 0.01 to about 10 mg / kg body weight / day. More typically from about 0.01 to about 5 mg / kg body weight / day. More typically from about 0.05 to about 0.5 mg / kg body weight / day. For example, a daily candidate dose for an adult weighing approximately 70 kg ranges from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of a single dose or multiple doses.

(Administration route)
One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) Including). It can be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of some embodiments of the invention is that they are orally bioavailable and can be dosed orally.

(Combination therapy)
The composition of the present invention is also used in combination with other active ingredients. Such combinations are selected based on the disease being treated, the component's interreactivity and the pharmacological properties of the formulation.

  It is also possible to combine any compound of the present invention with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient. This combination therapy can be administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered one or more times.

  This combination therapy may provide a “synergistic effect” and at least one “synergistic effect”, ie an effect that is higher than the sum of the effects resulting from the separate use of the compounds when the active ingredients are combined. Synergistic effects can be achieved when these active ingredients are: (1) when formulated together and administered or delivered together in a blended formulation; (2) alternately as separate formulations. Or when delivered in parallel; or (3) by some other regimen. When delivered in alternation therapy, these compounds may be achieved when administered or delivered by different injections sequentially (eg, in separate tablets, pills or capsules) or in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially (ie, sequentially), whereas in combination therapy, two or more effective dosages are administered together.

(Metabolite of the compound of the present invention)
Metabolites (eg, in vivo metabolites) of the compounds described herein are also within the scope of the invention. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound mainly due to enzymatic processes. Accordingly, the present invention includes compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce its metabolite. Such products typically prepare a radiolabeled (eg, ¹⁴ C or ³ H) compound of the invention and detect it in an animal (eg, rat, mouse, guinea pig, monkey or human) (E.g., a dose higher than about 0.5 mg / kg) parenterally gives sufficient time (typically about 30 seconds to 30 hours) to cause metabolism, and urine, It is identified by isolating its conversion product from blood or other biological sample. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind antigenic determinants remaining in the metabolite). The structure of the metabolite is determined by conventional methods (eg, MS or NMR analysis). In general, analysis of metabolites is performed in the same manner as normal drug metabolite studies well known to those skilled in the art. This conversion product is useful in diagnostic assays that therapeutically dose compounds of the present invention, even if they do not have their own kinase inhibitory activity, unless found in vivo.

  Strategies and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as being stable in the gastrointestinal tract when less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal fluid or gastric fluid when incubated at 37 ° C. for 1 hour. The Note that just because these compounds are stable in the gastrointestinal tract does not mean they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention are typically stable in the digestive system but are substantially hydrolyzed to their parent drug in the gastrointestinal tract, liver or other metabolic organs, or general cells. The

(Representative method for producing the compound of the present invention)
The invention also relates to a number of methods for preparing the compounds and compositions of the invention. These compounds and compositions are prepared by any applicable organic synthesis technique. Many such techniques are well known in the art. However, many of these known techniques are described in detail in the following document: “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr. 1980; Vol. 5, Leroy G. Wade, Jr. , 1984; and Vol. 6, Michael B.B. Smith; and March, J. et al. , "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis Selectivity, Strategy & Efficiency in Modern Organic Chemistry.In 9 Volumes", Barry M. Trost, Editor-in-Chief (printed in Pergamon Press, New York, 1993).

  Numerous representative methods of preparing the compounds and compositions of the invention are provided below. These methods are to be construed as illustrative of the nature of such preparations and are not to be construed as limiting the scope of the applicable methods.

(Scheme and Examples)
General aspects of these representative methods are described below and in the Examples. Each of the following process products is optionally separated, isolated and / or purified prior to use in subsequent processes.

  In general, reaction conditions such as temperature, reaction time, solvents, work-up procedures, etc. are common in the art for the particular reaction to be performed. The cited materials include a detailed description of such conditions, along with the materials cited herein. Typically, their temperature is -100 to 200 ° C, the solvent is aprotic or protic, and the reaction time is 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partitioning (extraction) between the water / organic layer system and separating the layers containing the product.

  While oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 ° C.), for metal hydride reduction, the temperature is often reduced from 0 ° C. to −100 ° C. The solvent is typically aprotic for reduction and can be either protic or aprotic for oxidation. The reaction time is adjusted to achieve the desired conversion.

  Condensation reactions are typically carried out at temperatures close to room temperature, but lower temperatures (0 ° C. to −100 ° C.) are also common for non-equilibrium and kinetically controlled condensations . The solvent can be either protic (which is common for equilibration reactions) or aprotic (which is common for kinetically controlled reactions).

  Standard synthetic techniques (eg, azeotropic removal of reaction byproducts and use of anhydrous reaction conditions (eg, inert gas environment)) are common in the art and are applied where applicable. Is done.

  The terms “treated”, “treating”, “treatment” and the like are used in connection with chemical synthesis operations to contact, mix, react. Means other terms customary in the art to indicate that contact is made and that one or more chemical elements are processed in a manner that converts them to one or more other chemical elements . This means that “treating compound 1 with compound 2” means “reacting compound 1 with compound 2”, “contacting compound 1 with compound 2”, “reacting compound 1 with compound 2” And the same meaning as other expressions customary in the technical field of organic synthesis, which rationally indicates “treatment”, “react”, “react”, etc., with compound 2. For example, “treating” means the usual rational way of reacting organic chemicals. Unless otherwise stated, normal concentrations (0.01M-10M, typically 0.1M-1M), temperatures (-100 ° C-250 ° C, typically -78 ° C-150 ° C, more typically Typically −78 ° C. to 100 ° C., even more typically 0 ° C. to 100 ° C.), reaction vessel (typically glass, plastic, metal), solvent, pressure, atmosphere (typically , Oxygen and water insensitive reactions are intended to be air, oxygen or water sensitive reactions argon) and the like. Similar reaction knowledge known in the art of organic synthesis is used in selecting conditions and equipment to “treat” in a given process. In particular, one skilled in the art of organic synthesis selects conditions and equipment that are reasonably expected to successfully perform the chemical reactions of the described process, based on knowledge in the art.

  Improvements to each of the exemplary schemes described above and in the examples (hereinafter “representative schemes”) provide various analogs of the specific exemplary materials produced. The above citations describing appropriate methods of organic synthesis are applicable to such modifications.

  In each of the exemplary schemes, it may be advantageous to separate reaction products from each other and / or from starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) by techniques common in the art until the desired degree of homogeneity. Typically such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography can include a number of methods including, for example: reverse phase and normal phase; size exclusion; ion exchange; high pressure, medium pressure and low pressure liquid chromatography methods and equipment; small scale Analysis; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as small thin layer and flash chromatography techniques.

  Other types of separation methods include treating the mixture with reagents that bind to or make separable the desired product, unreacted starting materials, reaction byproducts, and the like. Such reagents include adsorbents or absorbents (eg, activated carbon, molecular sieves, ion exchange media, etc.). Alternatively, these reagents include acids for basic substances, bases for acidic substances, binding reagents (eg, antibodies, binding proteins), selective chelating agents (eg, crown ethers, liquid / liquid ion exchange reagents ( LIX).

  The selection of an appropriate separation method depends on the nature of the substances involved. For example, boiling point and molecular weight during distillation and sublimation, presence or absence of polar functional groups during chromatography, stability of materials in acidic and basic media during multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.

  Single isomers substantially free of stereoisomers (eg, enantiomers) are obtained by resolution of their racemic mixture using methods such as the formation of diastereomers using optically active resolving agents. can get. ("Stereochemistry of Carbon Compounds" (1962) by EL Liel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) Formation of ionic diastereomeric salts using chiral compounds and fractional crystallization or other Separation by methods, (2) formation of diastereomeric compounds using chiral derivatization reagents, separation of these diastereomers and conversion to pure stereoisomers, and (3) substantial under chiral conditions Direct separation of pure or enriched stereoisomers.

  In method (1), the diastereomeric salt has an enantiomerically pure chiral base (eg, brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc.) and an acidic functional group. It can be formed by reaction with asymmetric compounds such as carboxylic acids and sulfonic acids. These diastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography. Addition of chiral carboxylic or sulfonic acids (eg camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid) to separate these optical isomers from amino compounds can form these diastereomeric salts.

  Alternatively, according to method (2), the substrate to be resolved is reacted with an enantiomer of the chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John). Wiley & Sons, Inc., p.322). Diastereomeric compounds are obtained by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent (eg, a menthyl derivative), followed by separation and hydrolysis of these diastereomers to yield the free enantiomer. It can be formed by obtaining a concentrated xanthene. The method for determining optical purity is in the presence of a base or Mosher ester, a racemic mixture thereof, α-methoxy-α- (trifluoromethyl) phenyl acetate (Jacob III. (1982) J. Org. Chem. 47: 4165). A process for preparing chiral esters (eg, menthyl esters (eg, (-) menthyl chloroformate)) and analyzing for the presence of two atropisomeric diastereomers in an NMR spectrum. . Stable diastereomers of atrop compounds can be separated and isolated by normal phase and reverse phase chromatography followed by separation of the atropisomeric naphthyl-isoquinoline (Hoye, T., WO 96/15111). According to method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513: 375-378). Enriched or purified enantiomers can be distinguished by the methods used to distinguish other chiral molecules with asymmetric carbon atoms (eg, optical rotation and circular dichroism).

(Example General section)
Numerous representative methods of preparing the compounds of the invention are provided herein, for example, in the following examples. These methods are to be construed as illustrative of the nature of such preparations and are not to be construed as limiting the scope of the applicable methods. Certain compounds of the present invention can be used as intermediates for preparing other compounds of the present invention. For example, the interconversion of various phosphonate compounds of the present invention is described below.

(Interconversion of phosphonate R-link-P (O) (OR ¹ ) ₂ , R-link-P (O) (OR ¹ ) (OH) and R-link-P (O) (OH) ₂ )
Schemes 32-38 below depict the preparation of phosphonate esters of the general structure R-link-P (O) (OR ¹ ) _2, where the R ¹ groups can be the same or different. The R ¹ group attached to the phosphonate ester or precursor thereof can be altered using established chemical transformations. The phosphonate interconversion reaction is illustrated in Scheme S32. The R group of Scheme 32, in any of the compounds of the invention or their precursors, represents a substructure (ie, the drug “scaffold”), where the substituent Link—P (O) (OR ¹ ₂ is bonded. During synthetic pathways that effect phosphonate interconversion, certain functional groups within R can be protected. The method used for a given phosphonate transformation depends on the nature of the substituent R ^{1 and} the nature of the substrate to which the phosphonate group is attached. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. et al. M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. It is described in 9ff.

  In general, the synthesis of phosphonate esters is accomplished by coupling a nucleophilic amine or alcohol with the corresponding activated phosphonate electrophilic precursor, for example, chlorophosphonate addition of a nucleoside to the 5′-hydroxy It is a well-known method for preparing nucleoside phosphonic acid monoesters. This activated precursor is prepared by several well-known methods. Chlorophosphonates useful for synthesizing these prodrugs are prepared from substituted 1,3-propanediol (Wissner et al. (1992) J. Med Chem. 35: 1650). Chlorophosphonates are prepared by oxidation of the corresponding chlorophosphorane (Anderson et al. (1984) J. Org. Chem. 49: 1304), which is obtained by reaction of a substituent diol with phosphorus trichloride. . Alternatively, the chlorophosphonate reagent is prepared by treating a substituted 1,3-diol with phosphorous oxychloride (Patois et al. (1990) J. Chem. Soc. Perkin Trans. 1, 1577). Chlorophosphonate species can also be generated in situ from the corresponding cyclic phosphites, which in turn can be prepared from either chlorophosphorane or phosphoramidate intermediates (Silverburg, et al. (1996). Tetrahedron lett., 37: 771-774). Phosphorofluoridate intermediates prepared from either pyrophosphate or phosphoric acid can also act as precursors in the preparation of cyclic prodrugs (Watanabe et al. (1988) Tetrahedron lett., 29: 5763-66). .

  The phosphonate prodrugs of the present invention can also be prepared from its free acid by the Mitsunobu reaction (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem., 57: 6331), and others These include carbodiimides (Alexander et al., (1994) Collect. Czech. Chem. Commun. 59: 1853; Casara et al., (1992) Bioorg. Med. Chem. Lett., 2 145; Ohashi et al., (1988) Tetrahedron Lett., 29: 1189), and benzotriazolyloxytris- (dimethylamino) phosphonium salt (Campagne et al., (1993) Tetrah. dron Lett, 34:. 6743) include, but are not limited to.

Aryl halides undergo Ni ⁺² catalyzed reaction with phosphite derivatives to give arylphosphonate-containing compounds (Balthazar et al. (1980) J. Org. Chem. 45: 5425). Phosphonates can also be prepared from this chlorophosphonate using an aromatic triflate in the presence of a palladium catalyst (Petrakis et al., (1987) J. Am. Chem. Soc. 109: 2831; Lu et al., (1987) Synthesis, 726). In other methods, phosphonic acid aryl esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22: 3375; Casteel et al. (1991) Synthesis, 691). N-alkoxyaryl salts with alkali metal derivatives of cyclic alkyl phosphonates provide a general synthesis of heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35: 4114). The above method can also be extended to compounds where the W ⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs of phosphonates can also be synthesized using a coupling reagent (eg, 1,3-dicyclohexylcarbodiimide (DCC)) in the presence of a base (eg, pyridine). Synthesized from acid and substituted propane-1,3-diol. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), another carbodiimide-based coupling reagent such as 1,3-diisopropylcarbodiimide or a water-soluble reagent, is also a cyclic phosphonate prodrug. Can be used for synthesis.

Conversion of the phosphonate diester S32.1 to the corresponding phosphonate monoester S32.2 (Scheme 32, Reaction 1) can be accomplished in a number of ways. For example, ester S32.1 (where R ¹ is an aralkyl group (eg, benzyl)) is described in J. Org. Org. Chem. , 1995, 60: 2946, can be converted to the monoester compound S32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine. This reaction is carried out at about 110 ° C. in an inert hydrocarbon solvent (eg, toluene or xylene). Conversion of the diester S32.1 (where R ¹ is an aryl group (eg, phenyl) or an alkenyl group (eg, allyl)) to the monoester S32.2 may result in the ester S32.1 being a base (eg, By treatment with aqueous sodium hydroxide solution in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. The phosphonate diester S32.1, where one of the R ¹ groups is aralkyl (eg benzyl) and the other is alkyl is converted to the monoester by hydrogenation using, for example, palladium over a carbon catalyst. Can be converted to S32.2, where R ¹ is alkyl. Phosphonate diesters in which both R ₁ groups are alkenyl (eg allyl) are described, for example, in J. Mol. Org. Chem. , 38: 3224 1973, using chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) in aqueous ethanol, optionally in the presence of diazabicyclooctane, at reflux. ) To give the monoester S32.2 where R ¹ is alkenyl.

Conversion of phosphonate diester S32.1 or phosphonate monoester S32.2 to the corresponding phosphonic acid S32.3 (Scheme 32, reactions 2 and 3) is described in J. Chem. Soc. , Chem. Comm. 739, (1979) by reacting this diester or monoester with trimethylsilyl bromide. This reaction is carried out in an inert solvent (eg, dichloromethane), optionally in the presence of a silylating agent (eg, bis (trimethylsilyl) trifluoroacetamide) at room temperature. The phosphonate monoester S32.2 (where R ¹ is aralkyl (benzyl)) is hydrogenated with a palladium catalyst or treated with hydrogen chloride in an ether-containing solvent (eg, dioxane). Can be converted to the corresponding phosphonic acid S32.3. Phosphonate monoester S32.2 (where R ¹ is alkenyl (eg allyl)) is described, for example, in Helv. Chim. Acta. , 68: 618, 1985 can be converted to phosphonic acid S32.3 by reaction with a Wilkinson catalyst in an aqueous organic solvent (eg, 15% aqueous acetonitrile or aqueous ethanol). . Palladium catalyzed hydrogenolysis of phosphonate ester S32.1 (where R ¹ is benzyl) is described in J. Am. Org. Chem. 24: 434, 1959. Platinum catalyzed hydrogenolysis of the phosphonate ester S32.1 (where R ¹ is phenyl) is described in J. Am. Amer. Chem. 78: 2336, 1956.

Conversion of phosphonate monoester S32.2 to phosphonate diester S32.1 (Scheme 32, Reaction 4) (wherein the newly introduced R ¹ group is alkyl, aralkyl, haloalkyl (eg, chloroethyl) or aralkyl) Can be carried out by a number of reactions in which the substrate S32.2 is reacted with a hydroxy compound R ¹ OH in the presence of a coupling agent. Typically, the second phosphonate ester group is different from the initially introduced phosphonate ester group, ie, R ² is introduced following R ¹ , where each of R ¹ and R ² is an alkyl , Aralkyl, haloalkyl (eg, chloroethyl) or aralkyl (Scheme 32, Reaction 4a), whereby S32.2 is converted to S32.1a. Suitable coupling agents include those used to prepare carboxylate esters, which include carbodiimides (eg, dicyclohexylcarbodiimide, in which case the reaction is preferably a basic organic Carried out in a solvent (e.g. pyridine)), or (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma) (in this case the reaction is carried out with a tertiary organic base (e.g. Carried out in a polar solvent (eg dimethylformamide) in the presence of diisopropylethylamine), or Aldrithiol-2 (Aldrich) (in this case the reaction is triarylphosphine (eg tonophenylphosphine)) In the presence of Medium (e.g., pyridine) in is performed) and the like. Alternatively, conversion of the phosphonate monoester S32.1 to the diester S32.2 is performed by using the Mitsunobu reaction as described above (Scheme 7). The substrate is reacted with the hydroxy compound R ¹ OH in the presence of diethyl azodicarboxylate and a triarylphosphine (eg triphenylphosphine). Alternatively, the phosphonate monoester S32.2 can be converted to the phosphonate diester S32.1 where the R ¹ group introduced by reacting the monoester with the halide R ¹ Br is alkenyl or arylalkyl; Here, R ¹ is alkenyl or arylalkyl. This alkylation reaction is carried out in a polar organic solvent (eg dimethylformamide or acetonitrile) in the presence of a base (eg cesium carbonate). Alternatively, the phosphonate monoester is converted to the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester S32.2 is prepared from Organic Phosphorus Compounds, G.M. M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. 17 can be converted to the chloro analog —P (O) (OR ¹ ) Cl by reaction with thionyl chloride or oxalyl chloride, etc., and the product thus obtained —P (O) (OR ¹ ) Cl is then reacted with the hydroxy compound R ¹ OH in the presence of a base (eg, triethylamine) to give the phosphonate diester S32.1.

Phosphonate R-Link-P (O) (OH) ₂ is a phosphonate diester R-Link-P (O) (OR ¹ ), except that only one molar proportion of component R ¹ OH or R ¹ Br is used. ₂ Can be converted to the phosphonate monoester RP (O) (OR ¹ ) (OH) (Scheme 32, Reaction 5) by the method described above to prepare S32.1. Dialkyl phosphonates can be prepared according to the following method: Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett. 3261; US 5663159.

Phosphonic acid R-link-P (O) (OH) ₂ S32.3 is coupled with a hydroxy compound R ¹ OH in the presence of a coupling agent (Aldrithiol-2 (Aldrich) and triphenylphosphine). Can be converted to phosphonate diester R-link-P (O) (OR ¹ ) ₂ S32.1 (Scheme 32, Reaction 6). This reaction is carried out in a basic solvent (eg pyridine). Alternatively, phosphonic acid S32.3 can be obtained by coupling reaction in pyridine at about 70 ° C. using, for example, phenol and dicyclohexylcarbodiimide, where phosphonic acid ester S32.1 (where R ¹ is aryl (eg , Phenyl). Alternatively, phosphonic acid S32.3 can be converted to a phosphonic acid ester S32.1 (where R ¹ is alkenyl) by an alkylation reaction. This phosphonic acid is reacted with an alkenyl bromide R ¹ Br in a polar organic solvent (eg acetonitrile solution) at reflux temperature in the presence of a base (eg cesium carbonate) to give the phosphonic acid ester S32 .1 is obtained.

  (Scheme 32)

（ホスホネートカーバメートの調製）
ホスホン酸エステルは、カーバメート連鎖を含有し得る。カーバメートの調製は、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，ｅｄ．，Ｐｅｒｇａｍｏｎ，１９９５，Ｖｏｌ．６，ｐ．４１６ｆｆおよびＯｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，ｂｙ Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６，ｐ．２６０ｆｆで記述されている。そのカルバモイル基は、Ｅｌｌｉｓ，ＵＳ ２００２／０１０３３７８ Ａ１ ａｎｄ Ｈａｊｉｍａ，ＵＳ ６０１８０４９の教示を含めて、当該技術分野で公知の方法に従って、水酸基の反応により、形成され得る。

(Preparation of phosphonate carbamate)
The phosphonate ester may contain carbamate linkages. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations, A.M. R. Katritzky, ed. Pergamon, 1995, Vol. 6, p. 416ff and Organic Functional Group Preparations, by S. R. Sandler and W.M. Karo, Academic Press, 1986, p. It is described at 260ff. The carbamoyl group can be formed by reaction of a hydroxyl group according to methods known in the art, including the teachings of Ellis, US 2002/0103378 A1 and Hajima, US 6018049.

  Scheme 33 illustrates various methods for synthesizing this carbamate chain. As shown in Scheme 33, in a general reaction to generate carbamate, alcohol S33.1 is converted to activated derivative S33.2 as described herein, where Lv is Leaving groups (eg, halo, imidazolyl, benzotriazoyl, etc.). The activated derivative S33.2 is then reacted with amine S33.3 to give the carbamate product S33.4. Examples 1-7 of Scheme 33 depict how to perform this general reaction. Examples 8-10 illustrate an alternative reaction to prepare carbamate.

  Scheme 33, Example 1 illustrates the preparation of carbamate using a chloroform derivative of alcohol S33.5. In this procedure, alcohol S33.5 is obtained from Org. Syn. Coll. Vol. 3,167,1965, reacted with phosgene in an inert solvent (eg, toluene) at about 0 ° C., or Org. Syn. Coll. Vol. Reacted with an equivalent reagent (eg, trichloromethoxychloroformate) to give chloroformate S33.6, as described in US Pat. The latter compound is then reacted with an amine component S33.3 in the presence of an organic or inorganic base to give carbamate S33.7. For example, chloroformyl compound S33.6 is obtained from Org. Syn. Coll. Vol. 3,167,1965, reacted with amine S33.3 in a water miscible solvent (eg, tetrahydrofuran) in the presence of aqueous sodium hydroxide to give carbamate S33.7. It is done. Alternatively, this reaction is carried out in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.

  Scheme 33, Example 2, depicts the reaction of chloroformate compound S33.6 with imidazole to produce imidazolide S33.8. This imidazolide product is then reacted with amine S33.3 to give carbamate S33.7. The preparation of the imidazolide is carried out at 0 ° C. in an aprotic solvent (eg dichloromethane) and the preparation of the carbamate is described in J. Am. Med. Chem. 1989, 32, 357 in a similar solvent at room temperature, optionally in the presence of a base (eg, dimethylaminopyridine).

  Scheme 33, Example 3, depicts the reaction of chloroformate S33.6 with activated hydroxyl compound R ″ OH to give mixed carbonate S33.10. This reaction can be accomplished using an inert organic solvent (eg, , Ether or dichloromethane) in the presence of a base (eg, dicyclohexylamine or triethylamine). The hydroxyl component R ″ OH can be converted to compounds S33.19-S33.24 and similar compounds shown in Scheme 33. Selected from the group of For example, if component R ″ OH is hydroxybenzotriazole S33.19, N-hydroxysuccinimide S33.20 or pentachlorophenol S33.21, it is described in Can. J. Chem., 1982, 60, 976. As shown, the reaction of this chloroformate with a hydroxyl compound in the presence of dicyclohexylamine in an ether-containing solvent gives mixed carbonate S33.10. Component R ″ OH is pentafluorophenol S33. A similar reaction which is 22 or 2-hydroxypyridine S33.23 is described in Syn. , 1986, 303, and Chem. Ber. 118, 468, 1985, in an ether-containing solvent in the presence of triethylamine.

Scheme 33, Example 4, illustrates the preparation of carbamates using alkyloxycarbonylimidazole S33.8. In this procedure, alcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare intermediate S33.8. This reaction is performed in an aprotic solvent (eg, dichloromethane or tetrahydrofuran). Acyloxyimidazole S33.8 is then reacted with an equimolar amount of amine R′NH ₂ to give carbamate S33.7. This reaction is described in Tet. Lett. , 42, 2001, 5227, in aprotic solvent (eg dichloromethane) to give carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamate with the intermediate alkoxycarbonylbenzotriazole S33.13. In this procedure, alcohol ROH is reacted with an equimolar amount of benzotriazole carbonyl chloride S33.12 at room temperature to give alkoxycarbonyl product S33.13. This reaction is described in Synthesis. 1977, 704 in an organic solvent (eg toluene) in the presence of a tertiary organic amine (eg triethylamine). The product is then reacted with amine R′NH ₂ to give carbamate S33.7. This reaction is described in Synthesis. 1977, 704 in toluene or ethanol at room temperature to about 80 ° C.

Scheme 33, Example 6, illustrates the preparation of carbamate, where carbonate (R ″ O) ₂ CO S33.14 is reacted with alcohol S33.5 to yield the intermediate alkyloxycarbonyl S33.15. The latter reagent is then reacted with amine R′NH ₂ to give carbamate S33.7 The procedure by which reagent S33.15 is derived from hydroxybenzotriazole S33.19 is described in Synthesis, 1993, The procedure by which reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet.Lett., 1992, 2781; reagent S33.15 is 2-hydroxypyridine S33. The procedure derived from .23 is Tet.Lett., 1991, 4251. The procedure by which reagent S33.15 is derived from 4-nitrophenol S33.24 is described in Synthesis, 1993, 103. Between equimolar amounts of alcohol ROH and carbonate S33.14. The reaction is carried out at room temperature in an inert organic solvent.

Scheme 33, Example 7, illustrates the preparation of carbamate from alkoxycarbonyl azide S33.16. In this procedure, alkyl chloroformate S33.6 is reacted with an azide (eg, sodium azide) to give alkoxycarbonyl azide S33.16. The latter compound is then reacted with an equimolar amount of amine R′NH ₂ to give carbamate S33.7. This reaction is described, for example, in Synthesis. , 1982, 404, at room temperature in a polar aprotic solvent (eg, dimethyl sulfoxide).

  Scheme 33, Example 8 illustrates the preparation of carbamate by reaction between alcohol ROH and the chloroformyl derivative of amine S33.17. In this procedure (which is described in Synthetic Organic Chemistry, RB Wagner, HD Zoo, Wiley, 1953, p. 647), the reactants are reacted at room temperature with an aprotic solvent (eg, , Acetonitrile) in the presence of a base (eg triethylamine) to give carbamate S33.7.

  Scheme 33, Example 9, illustrates the preparation of carbamate by reaction between alcohol ROH and isocyanate S33.18. In this procedure (which is described in Synthetic Organic Chemistry, RB Wagner, HD Zoo, Wiley, 1953, p.645), the reactants are reacted at room temperature with an aprotic solvent (eg, , Ether or dichloromethane) to give carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamate by reaction between alcohol ROH and amine R′NH ₂ . In this procedure (which is described in Chem. Lett. 1972, 373), the reaction is conducted at room temperature in an aprotic organic solvent (eg, tetrahydrofuran) with a tertiary base (eg, triethylamine). And in the presence of selenium. Carbon monoxide is passed through the solution, and the reaction proceeds to obtain carbamate S33.7.

(Scheme 33. Preparation of carbamate)
(General reaction)

（例）

(Example)

（カルボアルコキシ置換ホスホネートビスアミデート、モノアミデート、ジエステルおよびモノエステルの調製）
ホスホン酸をアミデートおよびエステルに変換する多数の方法が利用可能である。１群の方法では、このホスホン酸は、単離し活性化した中間体（例えば、塩化ホスホリル）に変換されるか、またはアミンまたはヒドロキシ化合物との反応のためにその場で活性化されるか、いずれかである。

Preparation of carboalkoxy substituted phosphonate bisamidates, monoamidates, diesters and monoesters
Numerous methods for converting phosphonic acids to amidates and esters are available. In one group of methods, the phosphonic acid is converted to an isolated and activated intermediate (eg, phosphoryl chloride) or activated in situ for reaction with an amine or hydroxy compound, Either.

  Conversion of phosphonic acid to phosphoryl chloride is described, for example, in J. Org. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim. , 1958, 28, 1063 or J.A. Org. Chem. , 1994, 59, 6144, by reaction with thionyl chloride or as described in J. Am. Am. Chem. Soc. , 1994, 116, 3251 or J.M. Org. Chem. , 1994, 59, 6144, by reaction with oxalyl chloride or as described in J. Am. Org. Chem. , 2001, 66, 329 or J.A. Med. Chem. , 1995, 38, 1372, either by reacting with phosphorus pentachloride. The resulting phosphoryl chloride is then reacted with an amine or hydroxy compound in the presence of a base to give these amidate or ester products.

  Phosphonic acid is described in J. Org. Chem. Soc. , Chem. Comm. (1991) 312 or Nucleosides & Nucleotides (2000) 19: 1885, which is converted to the activated imidazolyl derivative by reaction with carbonyldiimidazole. Activated sulfonyloxy derivatives can be obtained by reacting phosphonic acid with trichloromethylsulfonyl chloride or by Tet. Lett. (1996) 7857 or Bioorg. Med. Chem. Lett. (1998) 8: 663, obtained by reaction with triisopropylbenzenesulfonyl chloride. The activated sulfonyloxy derivative is then reacted with an amine or hydroxy compound to give an amidate or ester.

  Alternatively, the phosphonic acid and amine or hydroxy reactant are combined in the presence of a diimide coupling agent. The preparation of phosphonate amidates and esters by coupling reactions in the presence of dicyclohexylcarbodiimide is described, for example, in J. Am. Chem. Soc. , Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987) 52: 2792. The use of ethyldimethylaminopropylcarbodiimide to activate and couple phosphonic acids is described in Tet. Lett. (2001) 42: 8841 or Nucleosides & Nucleotides (2000) 19: 1885.

  A number of additional coupling reagents have been described for the preparation of amidates and esters from phosphonic acids. These reagents include Aldrithiol-2, and PYBOP and BOP (which are described in J. Org. Chem., 1995, 60, 5214 and J. Med. Chem. (1997) 40: 3842), Mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT) (these are described in J. Med. Chem. (1996) 39: 4958), diphenylphosphoryl azide (these are J. Org. Chem. (1984) 49: 1158), 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) (this is Bioorg. Med. Chem. Lett. (1998) 8: 1013). Bromotris (dimethylamino) phosphonium hexafluorophosphate (BroP) (which is described in Tet. Lett., (1996) 37: 3997), 2-chloro-5,5-dimethyl-2-oxo-1, 3,2-dioxaphosphinan (which is described in Nucleosides Nucleotides 1995, 14, 871), and diphenyl chlorophosphate (which is described in J. Med. Chem., 1988, 31, 1305). Is).

  Phosphonic acid is converted to amidate and ester by Mitsunobu reaction, where the phosphonic acid and amine or hydroxy reactant are combined in the presence of triarylphosphine and dialkyl azodicarboxylate. The procedure is described in Org. Lett. , 2001, 3, 643, or J.A. Med. Chem. 1997, 40, 3842.

  Phosphonate esters are also obtained by reaction between phosphonic acid and halo compounds in the presence of a suitable base. This method is described, for example, in Anal. Chem. , 1987, 59, 1056, or J.A. Chem. Soc. Perkin Trans. , I, 1993, 19, 2303, or J.I. Med. Chem. , 1995, 38, 1372, or Tet. Lett. 2002, 43, 1161.

  Schemes 34-37 show phosphonate esters and phosphonic acids to carboalkoxy substituted phosphorobisamidates (Scheme 34), phosphoramidates (Scheme 35), phosphonate monoesters (Scheme 36) and phosphonate diesters (Scheme 37). The conversion is illustrated. Scheme 38 illustrates the synthesis of gemi-dialkylaminophosphonate reagents.

Scheme 34 illustrates various methods for converting phosphonate diester S34.1 to phosphorobisamidate S34.5. Diester S34.1 (prepared as described above) is hydrolyzed to either monoester S34.2 or phosphonic acid S34.6. The method used for these transformations is described above. Monoester S34.2 is converted to monoamidate S34.3 by reaction with aminoester S34.9, wherein R ² group is H or alkyl; R ^4b group is divalent alkylene A moiety (eg, CHCH ₃ , CHCH ₂ CH ₃ , CH (CH (CH ₃ ) ₂ ), CH (CH ₂ Ph), etc.), or a side chain group present in a natural or modified amino acid; and R ^5b The groups are (C ₁ -C ₁₂ ) alkyl (eg, methyl, ethyl, propyl, isopropyl or isobutyl); (C ₆ -C ₂₀ ) aryl (eg, phenyl or substituted phenyl); or (C ₆ -C ₂₀ ) Arylalkyl (eg benzyl or benzhydryl). These reactants are optionally prepared in the presence of an activator (eg, hydroxybenzotriazole) in J. Am. Chem. Soc. (1957) 79: 3575, and mixed in the presence of a coupling agent (eg, carbodiimide (eg, dicyclohexylcarbodiimide)) to give the amidate product S34.3. This amidate formation reaction is also similar to BOP (which is described in J. Org. Chem. (1995) 60: 5214), Aldrithiol, PYBOP, and similar coupling agents used in the preparation of amides and esters. In the presence of Alternatively, reactants S34.2 and S34.9 are converted to monoamidate S34.3 by Mitsunobu reaction. Preparation of amidate by Mitsunobu reaction is described in J. Am. Med. Chem. (1995) 38: 2742. Equimolar amounts of these reactants are combined in an inert solvent (eg, tetrahydrofuran) in the presence of triarylphosphine and dialkylazodicarboxylate. The monoamidate ester S34.3 so obtained is then converted to amidate phosphonic acid S34.4. The conditions used for this hydrolysis reaction depend on the nature of the R ¹ group, as described above. The phosphonate amidate S34.4 is then reacted with the amino ester S34.9 as described above to give the bisamidate product S34.5, where the amino substituents are the same or different. Alternatively, phosphonic acid S34.6 can be treated simultaneously with two different aminoester reagents (ie, S34.9 with different R ² , R ^4b or R ^5b ). The resulting mixture of bisamidate products S34.5 may then be separable, for example by chromatography.

  (Scheme 34)

この手順の一例は、スキーム３４、例１で示す。この手順では、ホスホン酸ジベンジルＳ３４．１４は、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９５，６０，２９４６で記述されているように、トルエン中にて、還流状態で、ジアザビシクロオクタン（ＤＡＢＣＯ）と反応されて、ホスホン酸モノベンジルＳ３４．１５が得られる。次いで、その生成物は、ピリジン中にて、等モル量のアラニン酸エチルＳ３４．１６およびジシクロヘキシルカルボジイミドと反応されて、アミデート生成物Ｓ３４．１７が得られる。次いで、ベンジル基が、例えば、パラジウム触媒上での水素化分解によって除去されて、モノ酸生成物Ｓ３４．１８が得られ、これは、次いで、Ｊ．Ｍｅｄ．Ｃｈｅｍ．（１９９７）４０（２３）：３８４２に従って、不安定にされ得る。次いで、この化合物Ｓ３４．１８は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９５，３８，２７４２で記述されているように、光延反応にて、ロイシン酸エチルＳ３４．１９、トリフェニルホスフィンおよびジエチルアゾジカルボキシレートと反応されて、ビスアミデート生成物Ｓ３４．２０が得られる。

An example of this procedure is shown in Scheme 34, Example 1. In this procedure, dibenzyl phosphonate S34.14 Org. Chem. , 1995, 60, 2946, reacted with diazabicyclooctane (DABCO) in toluene at reflux to give monobenzyl phosphonate S34.15. The product is then reacted with equimolar amounts of ethyl alaninate S34.16 and dicyclohexylcarbodiimide in pyridine to give the amidate product S34.17. The benzyl group is then removed, for example by hydrogenolysis over a palladium catalyst, to give the monoacid product S34.18, which is then Med. Chem. (1997) 40 (23): 3842 can be destabilized. This compound S34.18 was then Med. Chem. , 1995, 38, 2742, in a Mitsunobu reaction with ethyl leucine S34.19, triphenylphosphine and diethylazodicarboxylate to give the bisamidate product S34.20.

  Using the above procedure, but using different aminoesters S34.9 instead of ethyl leucine S34.19 or ethyl alaninate S34.16, the corresponding product S34.5 is obtained.

  Alternatively, phosphonic acid S34.6 is converted to bisamidate S34.5 by using the above coupling reaction. This reaction is carried out in one stage (in this case the nitrogen-related substituents present in the product S34.5 are the same) or in two stages (in which case the nitrogen-related substituents can be different) The

  An example of this method is shown in Scheme 34, Example 2. In this procedure, phosphonic acid S34.6 is described, for example, in J. Org. Chem. Soc. , Chem. Comm. , 1991, 1063, is reacted with an excess of ethyl phenylalanate S34.21 and dicyclohexylcarbodiimide in a pyridine solution to give the bisamidate product S34.22.

  Using the above procedure, but using the different amino ester S34.9 instead of ethyl phenylalaninate, the corresponding product S34.5 is obtained.

  As yet another example, phosphonic acid S34.6 is converted to a mono or bis-active derivative S34.7, where Lv is a leaving group (eg, chloro, imidazolyl, triisopropylbenzenesulfonyloxy, etc.). . Conversion of phosphonic acid to chloride S34.7 (Lv = Cl) is described in Organic Phosphorus Compounds, G .; M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. As described in 17, it is carried out by reaction with thionyl chloride or oxalyl chloride. Conversion of phosphonic acid to monoimidazoline S34.7 (Lv = imidazolyl) is described in J. Am. Med. Chem. , 2002, 45, 1284 and J.A. Chem. Soc. Chem. Comm. 1991, 312. Alternatively, the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride as described in Nucleosides and Nucleotides, 2000, 10, 1885. The activated product is then reacted with amino ester S34.9 in the presence of a base to give bisamidate S34.5. This reaction can be performed in one step (in this case the nitrogen substituent present in the product S34.5 is the same) or in two steps via the intermediate S34.11 (in this case the nitrogen substituent is Can be different).

  Examples of these methods are shown in Scheme 34, Examples 3 and 5. In the procedure illustrated in Scheme 34, Example 3, the phosphonic acid S34.6 is prepared according to Zh. Obschei Khim. , 1958, 28, 1063 and reacted with 10 molar equivalents of thionyl chloride to give the dichloro compound S34.23. This product is then reacted with butyl selenate S34.24 in the presence of a base (eg triethylamine) in a polar aprotic solvent (eg acetonitrile) at reflux temperature to give the bisamidate product. S34.25 is obtained.

  Using the above procedure, but using a different amino ester S34.9 instead of butyl serinate S34.24, the corresponding product S34.5 is obtained.

  In the procedure illustrated in Scheme 34, Example 5, phosphonic acid S34.6 is prepared according to J. Am. Chem. Soc. Chem. Comm. , 1991, 312 and reacted with carbonyldiimidazole to give imidazolide S34.32. This product is then reacted with 1 molar equivalent of ethyl alaninate S34.33 in acetonitrile solution to give the mono-substituted product S34.34. The latter compound is then reacted with carbonyldiimidazole to produce the activated intermediate S34.35, which is then reacted with ethyl N-methylalaninate S34.33a under the same conditions. Thus, the bisamidate product S34.36 is obtained.

  Using the above procedure, but using a different amino ester S34.9 instead of ethyl alaninate S34.33 or N-methylalanine S34.33a, the corresponding product S34.5 is obtained.

The intermediate monoamidate S34.3 is also first converted to the monoester S34.2 by activating the derivative S34.8 (where Lv is a leaving group (eg halo, imidazolyl, etc.) using the above procedure. ). Product S34.8 is then reacted with amino ester S34.9 in the presence of a base (eg, pyridine) to give intermediate monoamidate product S34.3. The latter compound is then converted to bisamidate S34.5 by removing its R ¹ group and coupling the product with amino ester S34.9 as described above.

  An example of this procedure, where the phosphonic acid is activated by conversion to the chloro derivative S34.26, is shown in Scheme 34, Example 4. In this procedure, phosphonic acid monobenzyl ester S34.15 was prepared according to Tet. Let. , 1994, 35, 4097, reacted with thionyl chloride in dichloromethane to give phosphoryl chloride S34.26. This product is then reacted with 1 molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 in acetonitrile solution at room temperature to give the monoamidate product S34.28. The latter compound is hydrogenated in ethyl acetate with 5% palladium on carbon catalyst to give the monoacid product S34.29. This product was subjected to the Mitsunobu coupling procedure with equimolar amounts of butyl alaninate S34.30, triphenylphosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran to give the bisamidate product S34.31. It is done.

  Using the above procedure, but replacing the ethyl 3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30 with a different amino ester S34.9, the corresponding product S34.5 is can get.

The activated phosphonic acid derivative S34.7 is also converted to bisamidate S34.5 via the diamino compound S34.10. Conversion of an activated phosphonic acid derivative (eg, phosphoryl chloride) to the corresponding amino analog S34.10 by reaction with ammonia is described in Organic Phosphorus Compounds, G .; M.M. Kosolapoff, L.M. It is described by Maair, Wiley, 1976. The diamino compound S34.10 is then converted to the haloester in the presence of a base (eg 4,4-dimethylaminopyridine (DMAP) or potassium carbonate) in a polar solvent (eg dimethylformamide) at elevated temperature. Reaction with S34.12 (Hal = halogen, ie F, Cl, Br, I) gives the bisamidate S34.5. Alternatively, S34.6 can be treated simultaneously with two different aminoester reagents (ie, S34.12 with different R ^4b or R ^5b ). The resulting mixture of bisamidate products S34.5 may then be separable, for example by chromatography.

  An example of this procedure is shown in Scheme 34, Example 6. In this method, dichlorophosphonate S34.23 is reacted with ammonia to give diamide S34.37. This reaction is carried out at reflux temperature in an aqueous solution, aqueous alcohol solution or alcohol solution. The resulting diamino compound is then reacted in a polar organic solvent (eg, N-methylpyrrolidinone) at about 150 ° C. in the presence of a base (eg, potassium carbonate), and optionally as a catalyst. Reaction with 2 molar equivalents of ethyl 2-bromo-3-methylbutyrate S34.38 in the presence of an amount of potassium iodide gives the bisamidate product S34.39.

  Using the above procedure, but using a different haloester S34.12 instead of ethyl 2-bromo-3-methylbutyrate S34.38, the corresponding product S34.5 is obtained.

  The procedure shown in Scheme 34 is also applicable to the preparation of bisamidates, where the aminoester moiety incorporates different functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidates derived from tyrosine. In this procedure, monoimidazolide S34.32 is reacted with propyl tyrosine S34.40 as described in Example 5 to yield monoamidate S34.41. This product is reacted with carbonyldiimidazole to give imidazolide S34.42, which is reacted with an additional molar equivalent of propyl tyrosine to produce the bisamidate product S34.43.

  Using the above procedure, but using the different amino ester S34.9 instead of propyl tyrosine S34.40, the corresponding product S34.5 is obtained. The amino ester used in the two steps of the above procedure can be the same or different, so that bisamidates with the same or different amino substituents are prepared.

  Scheme 35 illustrates a method for preparing phosphonate monoamidate.

  In one procedure, the phosphonate monoester S34.1 is converted to the activated derivative S34.8 as described in Scheme 34. This compound is then reacted with the amino ester S34.9 in the presence of a base as described above to give the monoamidate product S35.1.

  This procedure is illustrated in Scheme 35, Example 1. In this method, monophenyl phosphonate S35.7 is described, for example, in J. Org. Gen. Chem. USSR. , 1983, 32, 367 and reacted with thionyl chloride to give the chloro product S35.8. This product is then reacted with ethyl alaninate as described in Scheme 34 to yield amidate S35.10.

  Using the above procedure, but using the different amino ester S34.9 instead of ethyl alaninate S35.9, the corresponding product S35.1 is obtained.

Alternatively, phosphonate monoester S34.1 is coupled with aminoester S34.9 as described in Scheme 34 to give amidate S35.1. If necessary, the R ¹ substituent is then changed by initial cleavage to give phosphonic acid S35.2. This transformation procedure depends on the nature of the R ¹ group and is described above. This phosphonic acid is then synthesized using the same coupling procedure described in Scheme 34 for amines and phosphonic acids (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu reaction, etc.) using the hydroxy compound R ³ OH (where R ³ The group is converted to the ester amidate product S35.3 by reaction with aryl, heterocycle, alkyl, cycloalkyl, haloalkyl, and the like.

  (Scheme 34, Example 1)

（スキーム３４、例２）

(Scheme 34, Example 2)

（スキーム３４、例３）

(Scheme 34, Example 3)

（スキーム３４、例４）

(Scheme 34, Example 4)

（スキーム３４、例５）

(Scheme 34, Example 5)

（スキーム３４、例６）

(Scheme 34, Example 6)

（スキーム３４、例７）

(Scheme 34, Example 7)

この方法の例は、スキーム３５、例１〜３で示している。例２で示した順序では、ホスホン酸モノベンジルＳ３５．１１は、上記方法の１つを使用して、アラニン酸エチルとの反応により、モノアミデートＳ３５．１２に変換される。そのベンジル基は、次いで、酢酸エチル溶液中にて、炭素上５％触媒で触媒水素化することにより除去されて、ホスホン酸アミデートＳ３５．１３が得られる。その生成物は、次いで、例えば、Ｔｅｔ．Ｌｅｔｔ．，２００１，４２，８８４１で記述されているように、ジクロロメタン溶液中にて、室温で、等モル量の１−（ジメチルアミノプロピル）−３−エチルカルボジイミドおよびトリフルオロエタノールＳ３５．１４と反応されて、アミデートエステルＳ３５．１５が生じる。

An example of this method is shown in Scheme 35, Examples 1-3. In the sequence shown in Example 2, monobenzyl phosphonate S35.11 is converted to monoamidate S35.12 by reaction with ethyl alaninate using one of the methods described above. The benzyl group is then removed by catalytic hydrogenation with 5% catalyst on carbon in ethyl acetate solution to give phosphonate amidate S35.13. The product can then be obtained, for example, from Tet. Lett. , 2001, 42, 8841 and reacted with equimolar amounts of 1- (dimethylaminopropyl) -3-ethylcarbodiimide and trifluoroethanol S35.14 in dichloromethane solution at room temperature. The amidate ester S35.15.

  In the sequence shown in Scheme 35, Example 3, monoamidate S35.13 is coupled with equimolar amounts of dicyclohexylcarbodiimide and 4-hydroxy-N-methylpiperidine S35.16 in tetrahydrofuran solution at room temperature. To produce the amidate ester product S35.17.

The above procedure is used, but instead of the ethyl alaninate product S35.12, a different monoacid S35.2 is used and trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16 is used. Instead, a different hydroxy compound R ³ OH is used to give the corresponding product S35.3.

Alternatively, activated phosphonate ester S34.8 is reacted with ammonia to yield amidate S35.4. This product is then reacted with the haloester S35.5 in the presence of a base as described in Scheme 34 to produce the amidate product S35.6. If appropriate, the nature of the R ¹ group is altered using the above procedure to give the product S35.3. This method is illustrated in Scheme 35, Example 4. In this order, monophenyl phosphoryl chloride S35.18 is reacted with ammonia as described in Scheme 34 to give the amino product S35.19. This material is then reacted with N-methylpyrrolidinone solution at 170 ° C. with butyl 2-bromo-3-phenylpropionate S35.20 and potassium carbonate to give the amidate product S35.21.

  Using these procedures, but using a different haloester S35.5 instead of butyl 2-bromo-3-phenylpropionate S35.20, the corresponding product S35.6 is obtained.

The monoamidate product S35.3 is also prepared from a doubly activated phosphonate derivative S34.7. In this procedure, an example is Synlett. , 1998, 1, 73, and intermediate S34.7 is reacted with a limited amount of amino ester S34.9 to give mono-substituted product S34.11. The latter compound is then reacted with the hydroxy compound R ³ OH in the presence of a base (eg diisopropylethylamine) in a polar organic solvent (eg dimethylformamide) to give the monoamidate ester S35.3. Occurs.

  This method is illustrated in Scheme 35, Example 5. In this method, phosphoryl dichloride S35.22 is reacted with 1 molar equivalent of ethyl N-methyltyrosinate S35.23 and dimethylaminopyridine in dichloromethane solution to yield monoamidate S35.24. This product is then reacted with phenol S35.25 in dimethylformamide containing potassium carbonate to yield the ester amidate product S35.26.

Using these procedures, but using the amino ester S34.9 and / or the hydroxy compound R ³ OH in place of the ethyl N-methyltyrosinate S35.23 or phenol S35.25, the corresponding product S35. 3 is obtained.

  (Scheme 35)

（スキーム３５、例１）

(Scheme 35, Example 1)

（スキーム３５、例２）

(Scheme 35, Example 2)

（スキーム３５、例３）

(Scheme 35, Example 3)

（スキーム３５、例４）

(Scheme 35, Example 4)

（スキーム３５、例５）

(Scheme 35, Example 5)

スキーム３６は、カルボアルコキシ置換ホスホネートジエステルを調製する方法を図示しており、ここで、それらのエステル基の１個は、カルボアルコキシ置換基を取り込む。

Scheme 36 illustrates a method of preparing carboalkoxy substituted phosphonate diesters, where one of those ester groups incorporates a carboalkoxy substituent.

In one procedure, the phosphonate monoester S34.1 (prepared as described above) is prepared using one of the methods described above, where the hydroxy ester S36.1 (where the R ^4b and R ^5b groups are As described in Scheme 34). For example, equimolar amounts of these reactants can be obtained from Aust. J. et al. Chem. , 1963, 609, in the presence of carbodiimide (eg, dicyclohexylcarbodiimide), as necessary, as described in Tet. , 1999, 55, 12997, in the presence of dimethylaminopyridine. This reaction is carried out in an inert solvent at room temperature.

  This procedure is illustrated in Scheme 36, Example 1. In this method, monophenyl phosphonate S36.9 was coupled with ethyl 3-hydroxy-2-methylpropionate S36.10 in the presence of dicyclohexylcarbodiimide in dichloromethane solution to produce phosphonate mixed diester S36. 11 is produced.

  Using this procedure, but using a different hydroxy ester 33.1 instead of ethyl 3-hydroxy-2-methylpropionate S36.10, the corresponding product 33.2 is obtained.

Conversion of phosphonate monoester S34.1 to mixed diester S36.2 is also described in Org. Lett. , 2001, 643, by Mitsunobu reaction with hydroxy ester S36.1. In this method, reactants S34.1 and S36.1 are combined in a polar solvent (eg, tetrahydrofuran) in the presence of a triarylphosphine and a dialkylazodicarboxylate to give mixed diester S36.2. can get. The R ¹ substituent is changed by cleavage using the method described above to give the monoacid product S36.3. This product is then coupled with the hydroxy compound R ³ OH, eg, using the method described above, to give the diester product S36.4.

  This procedure is illustrated in Scheme 36, Example 2. In this method, monoallyl phosphonate S36.12 is coupled with ethyl lactate S36.13 in tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to give mixed diester S36.14. It is done. This product is reacted with tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) in acetonitrile as described above to remove the allyl group and the monoacid product S36.15 is Generate. The latter compound is then coupled in pyridine solution at room temperature in the presence of dicyclohexylcarbodiimide with 1 molar equivalent of 3-hydroxypyridine S36.16 to give the mixed diester S36.17.

Using the above procedure, but using different hydroxy ester S36.1 and / or different hydroxy compound R ³ OH instead of ethyl lactate S36.13 or 3-hydroxypyridine, the corresponding product S36.4 is obtained. It is done.

  Mixed diester S36.2 is also obtained from monoester S34.1 via activated monoester S36.5. In this procedure, monoester S34.1 can be prepared, for example, according to J. Org. Chem. , 2001, 66, 329 by reaction with phosphorus pentachloride or in pyridine as described by Nucleosides and Nucleotides, 2000, 19, 1885 (thionyl chloride or oxalyl chloride ( Lv = Cl) or by reaction with triisopropylbenzenesulfonyl chloride, or J. Org. Med. Chem. , 2002, 45, 1284, which is converted to the activated compound S36.5 by reaction with carbonyldiimidazole. The resulting activated monoester is then reacted with the hydroxy ester S36.1 as described above to give the mixed diester S36.2.

  This procedure is illustrated in Scheme 36, Example 3. In this sequence, monophenyl phosphonate S36.9 is reacted with 10 equivalents of thionyl chloride in an acetonitrile solution at 70 ° C. to produce phosphoryl chloride S36.19. This product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containing triethylamine to give the mixed diester S36.21.

  Using the above procedure, but using different hydroxy ester S36.1 instead of ethyl 4-carbamoyl-2-hydroxybutyrate S36.20, the corresponding product S36.2 is obtained.

These mixed phosphonate diesters are also obtained by an alternative route of incorporating the R ³ O group into intermediate S36.3, where the hydroxy ester moiety has already been incorporated. In this procedure, the monoacid intermediate S36.3 is converted to the activated derivative S36.6 (where Lv is a leaving group (eg, chloro, imidazole, etc.)) as previously described. The The activated intermediate is then reacted with the hydroxy compound R ³ OH in the presence of a base to yield the mixed diester product S36.4.

  This method is illustrated in Scheme 36, Example 4. In this order, the phosphonate monoacid S36.22 is Med. Chem. , 1995, 38, 4648, is reacted with trichloromethanesulfonyl chloride in tetrahydrofuran containing collidine to produce the trichloromethanesulfonyloxy product S36.23. This compound is reacted with 3- (morpholinomethyl) phenol S36.24 in dichloromethane containing triethylamine to give the mixed diester product S36.25.

Using the above procedure, but using a different alcohol R ³ OH instead of 3- (morpholinomethyl) phenol S36.24, the corresponding product S36.4 is obtained.

  The phosphonate ester S36.4 is also obtained by an alkylation reaction carried out on the monoester S34.1. The reaction between the monoacid S34.1 and the haloester S36.7 can be carried out in a polar solvent in a base (eg diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or J Chem., 1995, 38, 1372, in the presence of triethylamine) or in a non-polar solvent such as benzene. Comm. , 1995, 25, 3565, in the presence of 18-crown-6.

  This method is illustrated in Scheme 36, Example 5. In this procedure, monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in dimethylformamide at 80 ° C. to give the mixed diester product S36.28. can get.

  Using the above procedure, but using the different haloester S36.7 instead of ethyl 2-bromo-3-phenylpropionate S36.27, the corresponding product S36.4 is obtained.

  (Scheme 36)

（スキーム３６、例１）

(Scheme 36, Example 1)

（スキーム３６、例２）

(Scheme 36, Example 2)

（スキーム３６、例３）

(Scheme 36, Example 3)

（スキーム３６、例４）

(Scheme 36, Example 4)

（スキーム３６、例５）

(Scheme 36, Example 5)

スキーム３７は、ホスホネートジエステルを調製する方法を図示しており、ここで、両方のエステル置換基は、カルボアルコキシ基を取り込む。

Scheme 37 illustrates a method for preparing phosphonate diesters, where both ester substituents incorporate a carboalkoxy group.

  These compounds are prepared directly or indirectly from phosphonic acid 1.6. In one alternative, the phosphonic acid is hydroxylated using conditions previously described in Schemes 34-36 (eg, coupling reactions using dicyclohexylcarbodiimide or similar reagents) or under Mitsunobu reaction conditions. Coupling with ester S37.2 yields diester product S37.3, where their ester substituents are the same.

  This method is illustrated in Scheme 37, Example 1. In this procedure, phosphonic acid S34.6 is reacted with 3 molar equivalents of butyl lactate S37.5 in pyridine at about 70 ° C. in the presence of Aldrithiol-2 and triphenylphosphine to give the diester S37. 6 is obtained.

  Using the above procedure, but using a different hydroxy ester S37.2 instead of butyl lactate S37.5, the corresponding product S37.3 is obtained.

  Alternatively, diester S37.3 is obtained by alkylating phosphonic acid S34.6 with haloester S37.1. This alkylation reaction is carried out as described in Scheme 3 for the preparation of ester S36.4.

  This method is illustrated in Scheme 37, Example 2. In this procedure, phosphonic acid S34.6 was prepared in Anal. Chem. , 1987, 59, 1056 are reacted with excess ethyl 3-bromo-2-methylpropionate S37.7 and diisopropylethylamine to produce the diester S37.8.

  Using the above procedure, but using the different haloester S37.1 instead of ethyl 3-bromo-2-methylpropionate S37.7, the corresponding product S37.3 is obtained.

  The diester S37.3 is also obtained by reaction of displacing the activated derivative S34.7 of this phosphonic acid with the hydroxy ester S37.2. This substitution reaction is performed as described in Scheme 3 in the presence of a suitable base in a polar solvent. This substitution reaction is carried out in the presence of excess hydroxy ester to give the diester product S37.3 (wherein the ester substituents are the same) or a limited amount of different hydroxy esters. To prepare diester S37.3, where their ester substituents are different.

  These methods are illustrated in Scheme 37, Examples 3 and 4. As shown in Example 3, phosphoryl dichloride S35.22 was reacted with 3 molar equivalents of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37.9 in tetrahydrofuran containing potassium carbonate. The diester product S37.10 is thus obtained.

  Using the above procedure, but using different hydroxy ester S37.2 instead of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37.9, the corresponding product S37.3 is obtained.

  Scheme 37, Example 4 depicts that a substitution reaction between equimolar amounts of phosphoryl chloride S35.22 and ethyl 2-methyl-3-hydroxypropionate S37.11 yields the monoester product S37.12. ing. This reaction is carried out in acetonitrile at 70 ° C. in the presence of diisopropylethylamine. Product S37.12 is then reacted with 1 molar equivalent of ethyl lactate S37.13 under the same conditions to give diester product S37.14.

  Using the above procedure, but using a continuous reaction with different hydroxy esters S37.2 instead of ethyl 2-methyl-3-hydroxypropionate S37.11 and ethyl lactate 4,13, the corresponding product S37 .3 is obtained.

  (Scheme 37)

（スキーム３７、例１）

(Scheme 37, Example 1)

（スキーム３７、例２）

(Scheme 37, Example 2)

（スキーム３７、例３）

(Scheme 37, Example 3)

（スキーム３７、例４）

(Scheme 37, Example 4)

２，２−ジメチル−２−アミノエチルホスホン酸中間体は、スキーム３８の経路により、調製できる。２−メチル−２−プロパンスルフィンアミドをアセトンで縮合すると、スルフィニルイミンＳ３８．１１が得られる（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９９，６４，１２）。Ｓ３８．１１にジメチルメチルホスホン酸リチウムを付加すると、Ｓ３８．１２が得られる。Ｓ３８．１２を酸性メタノール分解すると、アミンＳ３８．１３が得られる。アミンをＣｂｚ基で保護しメチル基を除去すると、ホスホン酸Ｓ３８．１４が生じ、これは、先に報告した方法を使用して、所望のＳ３８．１５（スキーム３８ａ）に変換できる。化合物Ｓ３８．１４の代替的な合成もまた、スキーム３８ｂで示されている。市販の２−アミノ−２−メチル−１−プロパノールは、文献方法（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９２，５７，５８１３；Ｓｙｎ．Ｌｅｔｔ．１９９７，８，８９３）に従って、アジリジンＳ３８．１６に変換される。ホスファイトをアジリジン開環すると、Ｓ３８．１７が得られる（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９８０，２１，１６２３）。Ｓ３８．１７を再保護すると、Ｓ３８．１４が得られる。

The 2,2-dimethyl-2-aminoethylphosphonic acid intermediate can be prepared by the route of Scheme 38. Condensation of 2-methyl-2-propanesulfinamide with acetone provides sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12). Addition of lithium dimethylmethylphosphonate to S38.11 yields S38.12. S38.12 is decomposed with acidic methanol to give amine S38.13. Protection of the amine with a Cbz group and removal of the methyl group yields phosphonic acid S38.14, which can be converted to the desired S38.15 (Scheme 38a) using previously reported methods. An alternative synthesis of compound S38.14 is also shown in Scheme 38b. Commercially available 2-amino-2-methyl-1-propanol is converted to aziridine S38.16 according to literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8, 893). . Opening the phosphite with aziridine yields S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotecting S38.17 gives S38.14.

  (Scheme 38a)

（スキーム３８ｂ）

(Scheme 38b)

本発明は、以下の非限定的な実施例により、例示される。

The invention is illustrated by the following non-limiting examples.

(General applicability of the method of introducing phosphonate substituents)
The procedures described herein for introducing phosphonate moieties can be transferred to different chemical substrates with appropriate modifications known to those skilled in the art. Therefore, the method described herein below for introducing a phosphonate group into a compound of the present invention is also applicable to the introduction of a phosphonate moiety into an aniline of the present invention, and vice versa.

(Protection of reactive substituents)
Depending on the reaction conditions used, according to the knowledge of the person skilled in the art, protecting certain reactive substituents from undesired reactions by protecting them before the described procedure, and removing these substituents later It may be necessary to protect. Functional group protection and deprotection are described, for example, in “Protective Groups in Organic Synthesis”, T.W. W. Greene and P.M. G. M Wuts, Wiley, Third Edition 1996. Reactive substituents that can be protected are shown in the accompanying schemes (eg, [OH], [SH], etc.).

Example 1
Pyridopyrimidine is a compound having activity against various kinases. Examples of this type of compound are PD 173955, PD 166326, and PD 173074.

  Compounds E1.1-E1.4 are representative compounds of the present invention where R and R 'are each independently hydrogen or alkyl.

（実施例２）
（式Ｅ１．１の代表的な化合物の合成）
一般に、式Ｅ１．１の化合物は、以下のようにして合成できる。

(Example 2)
(Synthesis of Representative Compounds of Formula E1.1)
In general, the compound of formula E1.1 can be synthesized as follows.

ホスホネートＥ１．１の調製は、上で図示されている（また、Ｋｌｕｔｃｈｋｏ，Ｓ．Ｒ．ｅｔ ａｌ．，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，４１，３２７６を参照のこと）。市販の５−ピリミジンカルボン酸エステルＥ２．１ｂと市販のアミノホスホネート（例えば、ホスホン酸アミノエチル）との縮合は、ＴＨＦ中で進行して、化合物Ｅ２．２ｂが得られる。そのエステル基を、エタノール中にて、ＮａＢＨ_４を使用して還元すると、ベンジルアルコールＥ２．３ｂが得られる（Ｐｆｅｉｆｆｅｒ，Ｆ．Ｒ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９７４，１７，１１２）。このアルコールのアルデヒドＥ２．４ｂへの酸化は、ＭｎＯ_２を使用して達成され、これは、次いで、ＤＭＦ中にて、高温で、置換フェニルアセトニトリルで縮合されて、７−イミノピリドピリミジンＥ２．５ｂが得られる。このイミンのアセチル化に続いて沸騰している６Ｎ ＨＣｌ下にて加水分解すると、重要な中間体Ｅ２．６ｂが得られる。不活性化アミンの添加は、チオエーテル Ｅ２．６ｂ上へと直接達成できるが、不活性化芳香族アミンは、さらに反応性のスルホキシドＥ２．７ｂまたはスルホンＥ２．８ｂと非常によく縮合される。このような中間体に加えられる芳香族アミンに依存して、ＰＤ １７３９５５およびＰＤ １８０９７０のホスホネート類似物が調製できる。

The preparation of phosphonate E1.1 is illustrated above (see also Klutchko, SR et al., J. Med. Chem., 1998, 41, 3276). Condensation of commercially available 5-pyrimidinecarboxylic acid ester E2.1b with a commercially available aminophosphonate (eg, aminoethyl phosphonate) proceeds in THF to give compound E2.2b. Reduction of the ester group in ethanol using NaBH ₄ gives benzyl alcohol E2.3b (Pfeiffer, FR et al., J. Med. Chem., 1974, 17, 112). Oxidation of this alcohol to aldehyde E2.4b is accomplished using MnO ₂ , which is then condensed with substituted phenylacetonitrile in DMF at elevated temperature to give 7-iminopyridopyrimidine E2. 5b is obtained. Hydrolysis under boiling 6N HCl following this imine acetylation yields the key intermediate E2.6b. The addition of the deactivated amine can be accomplished directly onto the thioether E2.6b, but the deactivated aromatic amine is also very well condensed with the reactive sulfoxide E2.7b or sulfone E2.8b. Depending on the aromatic amine added to such an intermediate, phosphonate analogs of PD 173955 and PD 180970 can be prepared.

(Example 3)
(Synthesis of Representative Compounds of Formula E1.2)
In general, the compound of formula E1.2 can be synthesized as follows.

  The compound provided below is an example of general structure E1.2, where the link comprises an alkyl group.

  As illustrated above, the condensation of alkylamines with sulfide E3.6a (reported in Klutchko, SR, et al., J. Med. Chem., 1998, 41, 3276) is enforced. Proceeding under conditions, the target compound is obtained.

Example 4
(Synthesis of Representative Compounds of Formula E1.3)
The synthesis of an example of an E1.3 type compound is illustrated below.

Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９７，４０，２２９６−２３０３で記載された手順に従って、出発物質（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９７，４０，２２９６−２３０３で記載された合成）であるスルファミン酸（２当量）および４−（ジエチルアミノ）ブチルアミン（約１５当量）を、１５０℃で、加熱する。この反応の終わりに、真空中で、過剰のアミンを除去する。残渣を、水および炭酸水素ナトリウム飽和水溶液の混合物に懸濁する。この混合物をジクロロメタンで抽出する。合わせた有機抽出物を、炭酸水素ナトリウム飽和水溶液、ブラインで洗浄し、そして硫酸ナトリウムで乾燥する。溶媒を濾過し蒸発させると、粗生成物が得られる。それ以上の精製は、シリカゲルフラッシュクロマトグラフィーにより達成した。

J. et al. Med. Chem. , 1997, 40, 2296-2303, and the starting materials (synthesis described in J. Med. Chem., 1997, 40, 2296-2303), sulfamic acid (2 equivalents) and 4- ( Diethylamino) butylamine (about 15 equivalents) is heated at 150 ° C. At the end of the reaction, excess amine is removed in vacuo. The residue is suspended in a mixture of water and saturated aqueous sodium bicarbonate. This mixture is extracted with dichloromethane. The combined organic extracts are washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solvent is filtered and evaporated to give the crude product. Further purification was achieved by silica gel flash chromatography.

The isocyanate required for Step 2 is prepared from 2-aminoethylphosphonic acid diethyl ester and phosgene according to the procedure of Organikum, 17 ^th edition, VEB Deutscher Verlag der Wissenshafen, Berlin 1988, page 428. To a cooled solution of phosgene in an organic solvent (eg, toluene or dichloromethane) is added a solution of 2-aminoethylphosphonic acid diethyl ester in an organic solvent (eg, dichloromethane or toluene). After the amine was added, the cooling was removed and the solution was heated at 100 ° C. with additional phosgene. When the evolution of hydrochloric acid ceased, excess phosgene was removed and the solvent was removed in vacuo.

  J. et al. Med. Chem. , 1997, 40, 2296-2303, the product of step 1 is treated with sodium hydride (about 1.1 equivalents) in an organic solvent (eg, dimethylformamide). The phosphonate-containing isocyanate is added and the reaction mixture is stirred at room temperature. At the end of the reaction, the mixture is filtered and the solvent removed in vacuo. The crude material is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic layers are washed with brine and dried over sodium sulfate. The solvent is filtered and evaporated to give the crude product. Further purification is achieved by silica gel flash chromatography.

  The synthesis of an example of an E1.4 type compound is illustrated below.

この上で記述したものと類似の方法を使用して、この合成を実行する。

This synthesis is performed using a method similar to that described above.

(Example 5)
(Preparation of representative compounds of the invention)
In general, the compounds of the present invention can be prepared as illustrated below:

６，７−ジメトキシ−３，４−ジヒドロキナゾリン−４−オンを三臭化ホウ素と反応させて、モノ−脱メチル化生成物の混合物を得る。これらの生成物の分離は、クロマトグラフィーにより達成され得るか、またはアセテートの混合物（これは、塩基（例えば、ピリジン）の存在下にて、アセチル化試薬（例えば、塩化アセチル）との反応から生じる）にて達成され得る。所望の異性体を塩化チオニルと反応させ（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，２００１，１１，１９１１を参照のこと）、得られた４−クロロキナゾリンをピペラジン−１−カルボン酸ベンジルエステルで処理する。標準的な条件下（例えば、メタノール中のアンモニアでの処理）にて、そのアセチル保護基を除去して（Ｇｒｅｅｎｅ，Ｔ．，Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ（１９９９）を参照のこと）、中間体Ｅ５．Ａを生成する。

6,7-dimethoxy-3,4-dihydroquinazolin-4-one is reacted with boron tribromide to give a mixture of mono-demethylated products. Separation of these products can be accomplished by chromatography or results from reaction with an acetylating reagent (eg, acetyl chloride) in the presence of a mixture of acetates (eg, pyridine). ). The desired isomer is reacted with thionyl chloride (see Bioorg. Med. Chem. Lett., 2001, 11, 1911) and the resulting 4-chloroquinazoline is treated with piperazine-1-carboxylic acid benzyl ester . Removal of the acetyl protecting group under standard conditions (eg treatment with ammonia in methanol) (see Greene, T., Protective Groups in Organic Synthesis, Wiley-Interscience (1999)). Intermediate E5. A is generated.

  When treated with a base (eg, magnesium tertiary butoxide and diethyl phosphonomethyltriflate), which was prepared according to Tetrahedron Lett., 1986, 27, 1477, the phosphonate-bearing moiety was converted to 7- Introduced into position. The benzyl carbamate protecting group is then removed by hydrogenation with a catalyst (eg palladium on charcoal) in a solvent (eg methanol) and 4-isopropoxyaniline (which is commercially available) ) And 4-nitrophenyl chloroformate to give the desired compound.

  Certain compounds of the invention can be prepared as follows.

Ｍｉｔｓｕｎｏｂｕ（Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊａｐａｎ．，１９７１，４４，３４２７）で記載されているように、中間体Ｅ５．Ａは、アゾジカルボン酸ジエステル（例えば、アゾジカルボン酸ジイソプロピル）およびトリフェニルホスフィンの存在下にて、４−（２−ヒドロキシ−エチル）−ピペラジン−１−カルボン酸第三級ブチルエステルとの反応により、フェノールにてアルキル化され得る。トリフルオロ酢酸で脱保護することに続いて、遊離された第二級アミンを、還元条件（例えば、シアノ水素化ホウ素ナトリウムを使用することにより達成される条件）下にて、溶媒（例えば、メタノールまたはジメチルホルムアミド）中で、（２−オキソ−エチル）−ホスホン酸ジエチルエステルと縮合する（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９０，３１，５５９５を参照のこと）。残りの工程は、上で図示したものと類似している。

Intermediate E5. As described by Mitsunobu (Bull. Chem. Soc. Japan., 1971, 44, 3427). A is reacted with 4- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid tert-butyl ester in the presence of azodicarboxylic acid diester (eg diisopropyl azodicarboxylate) and triphenylphosphine. Can be alkylated with phenol. Following deprotection with trifluoroacetic acid, the liberated secondary amine is removed under reduced conditions (eg, conditions achieved by using sodium cyanoborohydride) in a solvent (eg, methanol). Or dimethylformamide) with (2-oxo-ethyl) -phosphonic acid diethyl ester (see Tetrahedron Lett. 1990, 31, 5595). The remaining steps are similar to those illustrated above.

(Example 6)
(Synthesis of representative compounds of the present invention)
In general, the compounds of the present invention can be prepared as illustrated below:

選択的な脱メチル化に続いて、これらの合成工程は、フェノールがアルキル化される時点まで、実施例２で記述したものと類似している。ここで、このアルキル化は、Ｅ−１，４−ジブロモブテンを使って実行され、そのモノ臭化物生成物を、溶媒（例えば、トルエン）中で（または他のアルブーゾフ反応条件で；Ｅｎｇｅｌ，Ｒ．，Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ，ＣＲＣ Ｐｒｅｓｓ，（１９８８）を参照のこと）、亜リン酸トリエチルと反応させて、所望のホスホン酸のジエチルエステルを生成する。その後の工程は、実施例５で記述したものと類似している。

Following selective demethylation, these synthetic steps are similar to those described in Example 2 up to the point where the phenol is alkylated. Here, this alkylation is carried out using E-1,4-dibromobutene and the monobromide product is reacted in a solvent (eg toluene) (or other Arbuzov reaction conditions; Engel, R .; , Synthesis of Carbon-phosphorus Bonds, CRC Press, (1988)), and reaction with triethyl phosphite to produce the diethyl ester of the desired phosphonic acid. Subsequent steps are similar to those described in Example 5.

(Example 7)
(Synthesis of representative compounds of the present invention)
In general, the compounds of the present invention can be prepared as illustrated below:

４−ニトロフェノールを、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理する。泡立ちが止まると、ホスホノメチルトリフリック酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加え、所望のホスホン酸ジエステルが得られる。水素化してアニリンを生成することに続いて、公知の４−クロロ−６，７−ジメトキシ−キナゾリンで縮合すると、所望生成物が得られる。

4-Nitrophenol is treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceases, diethyl phosphonomethyltriflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired phosphonic diester. Following hydrogenation to produce aniline, condensation with known 4-chloro-6,7-dimethoxy-quinazoline gives the desired product.

(Example 8)
(Synthesis of representative compounds of the present invention)
In general, the compounds of the present invention can be prepared as illustrated below:

本発明の代表的な化合物は、例えば、上で示したように、以下の方法に従って、合成できる。３，４−ジフルオロ−２−（２−フルオロ−４−ヨードフェニルアミノ）安息香酸（これは、米国特許出願明細書２００４／００５４１７２で記載された手順に従って、得た）の活性化は、種々の通常の方法（これには、塩基（例えば、Ｎ−メチルモルホリン）の存在下にて溶媒（例えば、テトラヒドロフラン）中でのこの酸の塩化ジフェニルホスホリルでの初期処理が挙げられる）により、達成できる。ヒドロキサム酸エステルの引き続いた形成は、ＵＳ ２００４／００５４１７２で記載されたものと類似の条件下にて、この活性化された酸を、その場で、対応するホスホネート含有Ｎ−アルコキシアミンで処理することにより、達成できる。

Representative compounds of the present invention can be synthesized, for example, according to the following method, as shown above. Activation of 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzoic acid, which was obtained according to the procedure described in US patent application specification 2004/0054172, was observed in various ways. This can be accomplished by conventional methods, including initial treatment of this acid with diphenylphosphoryl chloride in a solvent (eg, tetrahydrofuran) in the presence of a base (eg, N-methylmorpholine). Subsequent formation of the hydroxamic acid ester involves treatment of the activated acid in situ with the corresponding phosphonate-containing N-alkoxyamine under conditions similar to those described in US 2004/0054172. Can be achieved.

  For example, the preparation of certain compounds of the present invention is illustrated below.

（Ｒ）−（＋）−３−ベンジルオキシ−１，２−プロパンジオールは、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００３，６８，６７６０で記載されているように、ｔ−ブチルジメチルシリル基で選択的に保護できる。得られた第二級アルコールは、塩基（例えば、マグネシウムｔ−ブトキシド）の存在下にて、ホスホノメチルトリフリック酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）と反応でき、このホスホネート含有エーテルが得られる。水素下での引き続いた脱ベンジル化に続いて、光延反応条件下にて、Ｎ−ヒドロキシフタルイミドとカップリングすると、Ｎ−アルコキシフタルイミドが得られ、これは、次いで、米国特許出願明細書２００４／００５４１７２，ｉｎ Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２０００，６５，６７６またはＪ．Ｍｅｄ．Ｃｈｅｍ．，２０００，４３，９７１で記載されているように、室温で、ヒドラジン（例えば、メチルヒドラジン）で処理することにより、Ｎ−アルコキシアミンに変換できる。このＮ−アルコキシアミンは、３，４−ジフルオロ−２−（２−フルオロ−４−ヨードフェニルアミノ）安息香酸とカップリングでき、ｔ−ブチルジメチルシリル基を除去した後、所望のヒドロキサメートが得られる。

(R)-(+)-3-Benzyloxy-1,2-propanediol is described in J. Am. Org. Chem. , 2003, 68, 6760 can be selectively protected with a t-butyldimethylsilyl group. The resulting secondary alcohol was prepared with diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) in the presence of a base (eg, magnesium t-butoxide). The phosphonate-containing ether can be obtained by reaction. Subsequent debenzylation under hydrogen followed by coupling with N-hydroxyphthalimide under Mitsunobu reaction conditions yields N-alkoxyphthalimide, which is then US Patent Application Publication 2004/0054172. , In J.H. Org. Chem. , 2000, 65, 676 or J.H. Med. Chem. , 2000, 43, 971, can be converted to N-alkoxyamines by treatment with hydrazine (eg, methyl hydrazine) at room temperature. This N-alkoxyamine can be coupled with 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzoic acid, and after removal of the t-butyldimethylsilyl group, the desired hydroxamate is can get.

  Another specific compound of the invention can be synthesized as follows:

Ｅｕｒ．Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００１，２０，３７９７で記載されているように、過剰の塩化ｔ−ブチルジメチルシリルで処理することにより、（Ｒ）−（＋）−３−ベンジルオキシ−１，２−プロパンジオールをビス−シリル化し、次いで、第一級ヒドロキシル基を選択的に脱シリル化する。得られた中間体を、塩基（例えば、マグネシウムｔ−ブトキシド）の存在下にて、ホスホノメチルトリフリック酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）と反応させて、ホスホネート含有エーテルを得る。この分子の残りは、上記と類似の様式で、合成する。

Eur. J. et al. Org. Chem. , 2001, 20, 3797 by treating with (R)-(+)-3-benzyloxy-1,2-propanediol by treatment with excess t-butyldimethylsilyl chloride. Silylation, and then selectively desilylating the primary hydroxyl groups. The resulting intermediate is reacted with diethyl phosphonomethyl triflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) in the presence of a base (eg, magnesium t-butoxide). To obtain a phosphonate-containing ether. The rest of this molecule is synthesized in a manner similar to that described above.

  Another specific compound of the invention can be synthesized as follows:

Ｎ−ヒドロキシフタルイミドを、塩基（例えば、炭酸セシウム）の存在下にて、ホスホノメチルトリフリック酸ジエチルと反応させて、ホスホネート含有Ｎ−アルコキシフタルイミドを得、これを、次いで、メチルヒドラジンにより、Ｎ−アルコキシアミンに変換される。このＮ−アルコキシアミンを３，４−ジフルオロ−２−（２−フルオロ−４−ヨードフェニルアミノ）安息香酸とカップリングして、所望のヒドロキサメートを得る。

N-hydroxyphthalimide is reacted with diethyl phosphonomethyltriflate in the presence of a base (eg, cesium carbonate) to give a phosphonate-containing N-alkoxyphthalimide, which is then converted with methylhydrazine to N -Converted to alkoxyamines. This N-alkoxyamine is coupled with 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzoic acid to give the desired hydroxamate.

Example 9
(Synthesis of representative compounds of the present invention)
In general, the compounds of the present invention can be prepared as illustrated below:

本発明の代表的な化合物は、例えば、上で示したように、以下の方法に従って、合成できる。２−（６−クロロ−２−メチルピリミジン−４−イルアミノ）チアゾール−５−カルボン酸（２−クロロ−６−メチルフェニル）アミド（これは、ＷＯ ００６２７７８で記載された手順に従って、２−アミノチアゾール−５−カルボン酸エチルエステルから得た）は、ピペラジンで処理でき、２−（２−メチル−６−ピペラジン−１−イルピリミジン−４−イルアミノ）チアゾール−５−カルボン酸（２−クロロ−６−メチルフェニル）アミドが得られる。このピペラジン誘導体を、アルデヒドとの還元アミノ化または臭化アルキルとのＮ−アルキル化のいずれかにより、Ｎ−置換して、所望のホスホネート含有生成物Ｅ９．１を得る。

Representative compounds of the present invention can be synthesized, for example, according to the following method, as shown above. 2- (6-Chloro-2-methylpyrimidin-4-ylamino) thiazole-5-carboxylic acid (2-chloro-6-methylphenyl) amide (which is a 2-aminothiazole according to the procedure described in WO0062778 -5-carboxylic acid ethyl ester) can be treated with piperazine to give 2- (2-methyl-6-piperazin-1-ylpyrimidin-4-ylamino) thiazole-5-carboxylic acid (2-chloro-6) -Methylphenyl) amide is obtained. This piperazine derivative is N-substituted by either reductive amination with an aldehyde or N-alkylation with an alkyl bromide to give the desired phosphonate-containing product E9.1.

  For example, the preparation of certain compounds of the present invention is illustrated below.

このピペラジン中間体は、無水エタノール中のジエチル（２−ブロモエチル）ホスホネートおよび炭酸ナトリウムの混合物に加えることができ、その混合物は、還流状態で、約１６時間加熱できる。得られた反応混合物は、シリカゲルクロマトグラフィーで精製でき、２−（ピペラジニル）エチルホスホン酸ジエチルが得られる（Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９８，４１，２３６−２４６）。

This piperazine intermediate can be added to a mixture of diethyl (2-bromoethyl) phosphonate and sodium carbonate in absolute ethanol, and the mixture can be heated at reflux for about 16 hours. The resulting reaction mixture can be purified by silica gel chromatography to give diethyl 2- (piperazinyl) ethylphosphonate (J. Med. Chem. 1998, 41, 236-246).

  Another specific compound of the invention can be synthesized as follows:

このクロロピリミジンは、（ＷＯ ００６２７７８で記載された手順と類似の手順に従って）、（ω−ヒドロキシアルキル）アミノピリミジンに変換でき、これは、次いで、臭素化に続いてアルブーゾフ反応を経由して、対応する（ω−ホスホノアルキル）アミノピリミジンＥ９．２に変換できる。

This chloropyrimidine can be converted to (ω-hydroxyalkyl) aminopyrimidine (following a procedure similar to that described in WO 0062778), which then undergoes the corresponding bronzation via the Arbuzov reaction. (Ω-phosphonoalkyl) aminopyrimidine E9.2 can be converted.

  For example, the preparation of certain compounds of the present invention is illustrated below.

クロロピリミジンおよびエタノールアミンの混合物は、約８０℃で、２時間加熱でき、この（２−ヒドロキシエチル）アミノピリミジンが得られる。次いで、そのヒドロキシル基は、通常の臭素化条件（例えば、四臭化炭素およびトリフェニルホスフィン）下にて、その臭化物に変換できる（Ｏｒｇ．Ｌｅｔｔ．２００３，５，３５１９）。この臭化物は、溶媒（例えば、トルエン）中で（または他のアルブーゾフ反応条件で：Ｅｎｇｅｌ，Ｒ．，Ｓｙｎｔｈｅｓｉｓ Ｏｆ Ｃａｒｂｏｎ−Ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ，ＣＲＣ ｐｒｅｓｓ，１９８８を参照）、アリン酸トリエチルと共に加熱でき、所望のホスホン酸のジエチルエステルが生成する。

The mixture of chloropyrimidine and ethanolamine can be heated at about 80 ° C. for 2 hours to give the (2-hydroxyethyl) aminopyrimidine. The hydroxyl group can then be converted to the bromide under normal bromination conditions (eg, carbon tetrabromide and triphenylphosphine) (Org. Lett. 2003, 5, 3519). The bromide can be heated in a solvent (eg, toluene) (or other Arbuzov reaction conditions: see Engel, R., Synthesis Of Carbon-Phosphorus Bonds, CRC press, 1988) with the desired triethyl allate. The diethyl ester of phosphonic acid is formed.

  Another specific compound of the invention can be synthesized as follows:

２−（２−アリル−６−ジメチルアミノ−ピリミジン−４−イルアミノ）チアゾール−５−カルボン酸（２−クロロ−６−メチル−フェニル）アミドは、ＷＯ ００６２７７８で記載された手順と類似の手順に従って、２−アミノチアゾール−５−カルボン酸エチルエステルから得ることができる。次いで、そのアリル基は、通常の化学方法（例えば、オレフィン交差メタセシスおよび酸化開裂に続いて還元アミノ化）により、その分子にホスホネート部分を結合するのに利用でき、ホスホネートＥ９．３のような化合物が得られる。

2- (2-Allyl-6-dimethylamino-pyrimidin-4-ylamino) thiazole-5-carboxylic acid (2-chloro-6-methyl-phenyl) amide follows a procedure similar to that described in WO0062778. 2-aminothiazole-5-carboxylic acid ethyl ester. The allyl group can then be utilized to attach a phosphonate moiety to the molecule by conventional chemical methods (eg, olefin cross-metathesis and oxidative cleavage followed by reductive amination), such as phosphonate E9.3. Is obtained.

  For example, the preparation of certain compounds of the present invention is illustrated below.

アリルピリミジン、ビニルホスホン酸ジエチルおよび５モル％の［１，３−ビス−（２，４，６−トリメチルフェニル）−２−イミダゾリジニリデン）ジクロロ（フェニルメチレン）−（トリクロロヘキシルホスフィン）ルテニウム］のジクロロメタン溶液は、１２時間還元でき、そして得られた反応混合物は、精製でき、所望のホスホネート含有化合物が得られる（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．２００３，１２５，１１３６０）。

Of allylpyrimidine, diethyl vinylphosphonate and 5 mol% [1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene) dichloro (phenylmethylene)-(trichlorohexylphosphine) ruthenium] The dichloromethane solution can be reduced for 12 hours and the resulting reaction mixture can be purified to give the desired phosphonate-containing compound (J. Am. Chem. Soc. 2003, 125, 11360).

  Another specific compound of the invention can be synthesized as follows:

２−｛２−アリル−６−［４−（２−ヒドロキシエチル）−ピペラジン−１−イル］−ピリミジン−４−イルアミノ｝−チアゾール−５−カルボン酸（２−クロロ−６−メチル−フェニル）−アミドは、ＷＯ ００６２７７８で記載された手順と類似の手順に従って、２−アミノチアゾール−５−カルボン酸エチルエステルから得ることができる。次いで、そのアリル基は、通常の化学方法（例えば、オレフィン交差メタセシスおよび酸化開裂に続いて還元アミノ化）により、その分子にホスホネート部分を結合するのに利用でき、ホスホネートＥ９．４のような化合物が得られる。

2- {2-allyl-6- [4- (2-hydroxyethyl) -piperazin-1-yl] -pyrimidin-4-ylamino} -thiazole-5-carboxylic acid (2-chloro-6-methyl-phenyl) The amide can be obtained from 2-aminothiazole-5-carboxylic acid ethyl ester according to a procedure similar to that described in WO0062778. The allyl group can then be utilized to attach the phosphonate moiety to the molecule by conventional chemical methods (eg, olefin cross-metathesis and oxidative cleavage followed by reductive amination), such as phosphonate E9.4. Is obtained.

  For example, the preparation of certain compounds of the present invention is illustrated below.

アリルピリミジン、ビニルホスホン酸ジエチルおよび５モル％の［１，３−ビス−（２，４，６−トリメチルフェニル）−２−イミダゾリジニリデン）ジクロロ（フェニルメチレン）−（トリクロロヘキシルホスフィン）ルテニウム］のジクロロメタン溶液は、１２時間還元でき、そして得られた反応混合物は、精製でき、所望のホスホネート含有化合物が得られる（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．２００３，１２５，１１３６０）。

Of allylpyrimidine, diethyl vinylphosphonate and 5 mol% [1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene) dichloro (phenylmethylene)-(trichlorohexylphosphine) ruthenium] The dichloromethane solution can be reduced for 12 hours and the resulting reaction mixture can be purified to give the desired phosphonate-containing compound (J. Am. Chem. Soc. 2003, 125, 11360).

(Example 10)
(Synthesis of representative compounds of the present invention)
In general, the compounds of the present invention can be prepared as illustrated below:

本発明の代表的な化合物は、例えば、上で示したように、以下の方法に従って、合成できる。［３−（４−ブロモ−２，６−ジフルオロ−ベンジルオキシ）−４−カルバモイル−イソチアゾール−５−イル］−カルバミン酸フェニルエステル（これは、ＷＯ ０９９６２８９０に従って、調製した）は、不活性溶媒（例えば、ＴＨＦ）中にて、（２−アミノ−エチル）−ホスホン酸ジエチルエステルと共に加熱でき、所望生成物が生成する。

Representative compounds of the present invention can be synthesized, for example, according to the following method, as shown above. [3- (4-Bromo-2,6-difluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl] -carbamic acid phenyl ester (prepared according to WO 09962890) is an inert solvent Can be heated with (2-amino-ethyl) -phosphonic acid diethyl ester in (e.g., THF) to produce the desired product.

(Example 11)
(Synthesis of representative compounds of the present invention)
3-Substituted indolinones are a class of compounds that have activity against various kinases. Examples of this type of compound include Semaxanib, SU-11248, and GW 9499.

  Compounds E11.1-E11.3 are representative compounds of the invention where R and R 'are each independently hydrogen or alkyl.

（実施例１２）
（本発明の代表的な化合物の合成）
一般に、Ｅ１１．１のような化合物は、以下で概説する一般経路に従って、製造できる。

(Example 12)
(Synthesis of representative compounds of the present invention)
In general, compounds such as E11.1 can be prepared according to the general route outlined below.

本発明の特定の化合物は、以下のようにして、調製できる：

Certain compounds of the invention can be prepared as follows:

Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００３，４６，１１１６で記載されているようにして、アセト酢酸ｔ−ブチルから、５−（５−フルオロ−２−オキソ−１，２−ジヒドロ−インドール−３−イリデンメチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボン酸を調製する。次いで、アミド形成試薬（例えば、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（ＥＤＣ）および１−ヒドロキシベンゾトリアゾール（ＨＯＢｔ））を使用することにより、この酸をホスホネート含有アミンと縮合して、所望生成物を得る。

J. et al. Med. Chem. From t-butyl acetoacetate to 5- (5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidenemethyl) -2,4-dimethyl as described in 2003, 46, 1116. -1H-pyrrole-3-carboxylic acid is prepared. The acid is then condensed with a phosphonate-containing amine by using an amide-forming reagent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt). To obtain the desired product.

(Example 13)
(Synthesis of representative compounds of the present invention)
In general, the compound of formula E11.2 can be synthesized as follows.

（実施例１４）
（本発明の代表的な化合物の合成）
Ｅ１１．３型の化合物の一例の合成は、以下で図示する。

(Example 14)
(Synthesis of representative compounds of the present invention)
The synthesis of an example of an E11.3 type compound is illustrated below.

塩化４−ニトロフェニルスルホニルと（２−アミノ−エチル）−ホスホン酸ジエチルエステルとの縮合に続いて、ジアゾ化および亜硫酸ナトリウム（Ｃｈｅｍ．Ｂｅｒ．，１９６０，９３，５４０）または塩化スズ（ＩＩ）（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，４０３１）での還元により、そのニトロ基をアリールヒドラジンに変換する。次いで、この試薬を、ＷＯ０９９１５５００で記載されているように、６Ｈ−チアゾロ［５，４−ｅ］インドール−７，８−ジオンと縮合して、所望生成物を生成する。

Following condensation of 4-nitrophenylsulfonyl chloride with (2-amino-ethyl) -phosphonic acid diethyl ester, diazotization and sodium sulfite (Chem. Ber., 1960, 93, 540) or tin (II) chloride ( J. Med. Chem., 2001, 44, 4031), the nitro group is converted to an aryl hydrazine. This reagent is then condensed with 6H-thiazolo [5,4-e] indole-7,8-dione as described in WO09915500 to produce the desired product.

(Example 15)
(Synthesis of representative compounds of the present invention)

この経路は、ＷＯ ０３０４０１３１で記載されたものと類似している。塩基（例えば、水素化ナトリウム）を使用して、溶媒（例えば、ジメチルホルムアミド）中で、（４−ヒドロキシ）安息香酸メチルとホスホノメチルトリフリック酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）との反応により、この（４−クロロカルボニル−フェノキシメチル）−ホスホン酸ジエチルエステルを合成し、続いて、水酸化リチウムでエステルケン化し、そのカルボン酸を、ジクロロメタン中で、触媒量のジメチルホルムアミドの存在下にて、塩化オキサリルで処理することにより、酸塩化物を形成する。

This route is similar to that described in WO 03040131. Methyl (4-hydroxy) benzoate and diethyl phosphonomethyltriflate (which is Tetrahedron Lett., 1986, 27) in a solvent (eg, dimethylformamide) using a base (eg, sodium hydride). This (4-chlorocarbonyl-phenoxymethyl) -phosphonic acid diethyl ester was synthesized by reaction with lithium hydroxide, followed by esterification with lithium hydroxide and the carboxylic acid in dichloromethane. The acid chloride is formed by treatment with oxalyl chloride in the presence of a catalytic amount of dimethylformamide.

(Example 16)
(Synthesis of representative compounds of the present invention)

この経路は、ＷＯ ０３０４０１３１で記載されたものと類似している。塩基（例えば、水素化ナトリウム）を使用して、溶媒（例えば、ジメチルホルムアミド）中で、（４−ヒドロキシ）安息香酸メチルとホスホノメチルトリフリック酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）との反応により、この（４−クロロカルボニル−フェノキシメチル）−ホスホン酸ジエチルエステルを合成し、続いて、水酸化リチウムでエステルケン化し、そのカルボン酸を、ジクロロメタン中で、触媒量のジメチルホルムアミドの存在下にて、塩化オキサリルで処理することにより、酸塩化物を形成する。

This route is similar to that described in WO 03040131. Methyl (4-hydroxy) benzoate and diethyl phosphonomethyltriflate (which is Tetrahedron Lett., 1986, 27) in a solvent (eg, dimethylformamide) using a base (eg, sodium hydride). This (4-chlorocarbonyl-phenoxymethyl) -phosphonic acid diethyl ester was synthesized by reaction with lithium hydroxide, followed by esterification with lithium hydroxide and the carboxylic acid in dichloromethane. The acid chloride is formed by treatment with oxalyl chloride in the presence of a catalytic amount of dimethylformamide.

(Example 17)
(Synthesis of representative compounds of the present invention)

この（３−クロロ−フェニル）−［４−（２−クロロ−ピリジン−４−イル）−ピリミジン−２−イル］−アミンを、ＷＯ０１０９３６８２で記載されているようにして、ジオキサン中で（２−アミノ−エチル）−ホスホン酸ジエチルエステルと共に加熱して、所望生成物を生成する。

This (3-chloro-phenyl)-[4- (2-chloro-pyridin-4-yl) -pyrimidin-2-yl] -amine is prepared in dioxane as described in WO01093682 (2- Heat with amino-ethyl) -phosphonic acid diethyl ester to produce the desired product.

(Example 18)
(Synthesis of representative compounds of the present invention)

ＷＯ０１０９３６８２で記載された方法と類似の方法により、この３−｛４−［２−（３−ブロモ−フェニルアミノ）−ピリミジン−４−イル］−ピリジン−２−イルアミノ｝−プロパン−１−オールを合成する。ソノガシラ（Ｓｏｎｏｇａｓｈｉｒａ）（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９７５，４４６７）により記載された条件下にて、ブタ−３−イニル−ホスホン酸ジエチルエステル（これは、溶媒（例えば、トルエン）中で、または他のアルブーゾフ反応条件で（Ｅｎｇｅｌ，Ｒ．，Ｓｙｎｔｈｅｓｉｓ ｏｆ ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ ｂｏｎｄｓ，ＣＲＣ ｐｒｅｓｓ，１９８８を参照のこと）、１−ブロモブタ−３−インを亜リン酸トリエチルと共に加熱することにより、調製した）とのパラジウム触媒カップリングすると、所望生成物が得られる。

This 3- {4- [2- (3-bromo-phenylamino) -pyrimidin-4-yl] -pyridin-2-ylamino} -propan-1-ol is prepared by a method similar to that described in WO01093682. Synthesize. Under the conditions described by Sonogashira (Tetrahedron Lett., 1975, 4467), but-3-ynyl-phosphonic acid diethyl ester (which is a solvent such as toluene) or other Arbuzov reactions Palladium catalyst under conditions (see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) prepared by heating 1-bromobut-3-yne with triethyl phosphite) Upon coupling, the desired product is obtained.

  The contents of all references and patent citations listed herein are incorporated by reference in the place of those patent citations. The contents of the specifically cited sections or pages of the cited study are specifically incorporated by reference. The present invention has been described in sufficient detail to enable those skilled in the art to make and use the objects of the above embodiments. It will be apparent that certain modifications to the methods and compositions of the above embodiments may fall within the scope and spirit of the invention.

In the above embodiment, the subscript and superscript of the predetermined variable are different. For example, R ₁ is different from R ¹ .

Claims (68)

A compound comprising at least one phosphonate group and a substructure of any one of formulas 100 to 106, or a pharmaceutically acceptable salt thereof:

here:

The bond represented by is a single bond or a double bond;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl; and R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² are taken together with the nitrogen atom to which they are attached. Form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁶ is —N— or —CR ⁶⁸ ; and R ⁶⁸ is hydrogen or alkyl.
A compound, or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 comprising a substructure of any one of formula II to formula XVII, or a pharmaceutically acceptable salt thereof:

here:
Each R ³⁹ and R ⁴⁰ is independently hydrogen, fluorine, chlorine, bromine or iodine;
na and ma are each independently 1, 2, 3 or 4;
R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently hydrogen, fluorine, chlorine, bromine or iodine;
R ⁴⁵ is hydrogen, —NH— (C ₆ -C ₂₀ ) aryl or —NH-substituted (C ₆ -C ₂₀ ) aryl;
A _a is a carbocyclic or heterocyclic ring;
R ⁴⁶ is a substituted heterocycle;
R ⁴⁹ is hydrogen, — (C ₆ -C ₂₀ ) aryl or — (C ₆ -C ₂₀ ) -substituted aryl;
R ⁵⁰ is hydrogen, substituted alkyl, or —C (═O) NR ⁵¹ R ⁵² ;
R ⁵¹ and R ⁵² are independently hydrogen, alkyl, or substituted alkyl;
R ⁵⁵ is a bond or alkylene;
R ⁵⁶ is —N— or —CR ⁵⁷ —;
R ⁵⁷ is hydrogen or alkyl;
R ⁵⁸ is hydrogen, halo, alkyl, fused carbocycle or fused heterocycle;
And R ^59, = ^{CR 64} - or = ^{N-NR 64} - is;
R ⁶⁰ is phenyl or pyrrolyl;
Each R ⁶¹ is independently an alkyl or polar group;
Each R ⁶⁴ is independently hydrogen or alkyl;
R ⁶⁷ is substituted aryl; and nb is 0, 1, 2, or 3.
A compound, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, comprising a substructure of formulas 1-24, or a pharmaceutically acceptable salt thereof:

here:
A ⁰ is A ¹ ;
A ¹ is:

A ³ are the following:

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3 is} a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{-S (O) 2 (OR x}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{Y 1) R x, -SC (} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ²¹ is substituted alkyl or substituted aryl;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl;
R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁸ is hydrogen or halo;
R ⁶⁵ is hydrogen, alkyl or halo; and R ⁶⁶ is a carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A ⁰ ;
A compound, or a pharmaceutically acceptable salt thereof. A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups,
Compound. The compound according to claim 3, wherein M12a is 1. A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocycle, which is independently substituted with 0 or 1 R ² groups,
Compound. A ¹ is a formula: A compound according to claim 3:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocycle, which is independently substituted with 0 or 1 R ² groups,
Compound. A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups,
Compound. A ¹ is a formula: A compound according to claim 3:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ^x ),
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. 23. The compound of claim 22, wherein M12d is 1. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

W ⁵ is a carbocycle, a compound according to claim 25. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

W ⁵ is phenyl, A compound according to claim 27. 29. The compound of claim 28, wherein M12b is 1. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ^x ),
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. 33. The compound of claim 32, wherein R < ¹ > is H. 35. The compound of claim 32, wherein M12d is 1. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups,
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Where R ¹ is independently H or alkyl of 1 to 18 carbon atoms,
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^1a is O or S;
Y ^2b is O or N (R ² );
Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ² ),
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^1a is O or S;
Y ^2b is O or N (R ² );
Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound. The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^2b is O or N (R ² ),
Compound. A ⁰ is a the formula A compound according to claim 3:

Where each R is independently (C ₁ -C ₆ ) alkyl.
Compound. 53. A compound according to any one of claims 1 to 52, isolated and purified. Serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase and / or EGF 54. The compound of any one of claims 1 to 53, which inhibits receptor tyrosine kinase. 55. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to any one of claims 1 to 54. 55. A unit dosage form containing a compound according to any one of claims 1 to 54 and a pharmaceutically acceptable excipient. 55. A method of inhibiting a kinase in vitro or in vivo comprising contacting a sample in need of such treatment with a compound according to any one of claims 1-54. 58. The method of claim 57, wherein the contacting is made in vivo. 55. A method of inhibiting a kinase in a mammal comprising administering to the mammal a compound according to any one of claims 1 to 54. 60. The method of claim 59, wherein the compound is formulated with a pharmaceutically acceptable carrier. 61. The method of claim 60, wherein the formulation contains a second active ingredient. The kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase. 62. The method of any one of claims 57 to 61, wherein the method is and / or EGF receptor tyrosine kinase. 55. A method of treating cancer in a patient in need of such treatment comprising administering to said patient a compound according to any one of claims 1-54. 55. A compound according to any one of claims 1 to 54 for use in medical therapy. 66. Use of a compound according to claim 65 for the preparation of a medicament that inhibits a kinase in an animal. The kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase. 66. Use according to claim 65, which is and / or an EGF receptor tyrosine kinase. 55. Use of a compound according to any one of claims 1 to 54 for the preparation of a medicament for treating cancer in an animal. Methods for preparing the compounds described in the schemes and examples herein.